CN102548995A - Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation - Google Patents

Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation Download PDF

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CN102548995A
CN102548995A CN201080045470XA CN201080045470A CN102548995A CN 102548995 A CN102548995 A CN 102548995A CN 201080045470X A CN201080045470X A CN 201080045470XA CN 201080045470 A CN201080045470 A CN 201080045470A CN 102548995 A CN102548995 A CN 102548995A
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quinoline
methyl
pyridazine
alkyl
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CN102548995B (en
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富兴年
贺峰
李悦
刘磊
米沅
徐耀昌
寻国良
Z·于
J·Y·(J)·张
戴淼
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Novartis AG
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Novartis AG
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Abstract

The invention relates to compounds of formula (I) and salts thereof: wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).

Description

The purposes of heterocycle hydrazone compound and their treatment cancers and inflammation
The present invention relates to the purposes of bicyclic compound and salt, said compounds for treating human body or the animal body of formula (I), particularly treat proliferative disease purposes, comprise said compound pharmaceutical composition, comprise the method for formula (I) combination of compounds and the said compound of preparation.
PHGF (this paper is called c-Met) is a receptor tyrosine kinase; Verified its crossed in various malignant diseases and expressed and/or the developmental genetics change; Particularly, gene amplification and a large amount of c-Met sudden changes in various solid tumors, have been found, referring to for example WO2007/126799.In addition, receptor tyrosine kinase c-Met participates in following embryo's generation and tissue regeneration and the migration, invasion and attack and the morphogenetic process that occur.C-met also participates in transfer process.Multidirectional evidence shows that c-Met plays a role in tumor invasion mechanism.The acquisition of the function germ line mutation of c-Met is relevant with the generation of heredity (hereditary) Papillary Renal Cell Carcinoma (PRCC).The amplification or the sudden change that have c-Met in sporadic form (sporadic form of PRCC), neck squamous cell carcinoma, cancer of the stomach, carcinoma of the pancreas and the lung cancer of PRCC also have been reported in.Verified this type change makes tumour depend on c-Met and/or other targeted therapy is produced resistance in situation about selecting.Observed the level rising of c-Met together with its unique part HGF/SF the tumour high frequency of on various clinical, being correlated with.In the multiple cancer that comprises bladder cancer, breast cancer, squamous cell carcinoma and cancer of the stomach and leiomyosarcoma and glioblastoma, reported and expressed the cognation between increase and PD, transfer and the mortality.
WO 2008/008539 discloses some condensed heterocyclic derivates, and it can be used for treating the disease of HGF mediation.WO 2007/013673 discloses the condensed heterocyclic derivates as the Lck suppressor factor, its useful as immunosuppressants.EP0490587 discloses some Pyrazolopyrimidine compound, and it can be used as the Angiotensin II antagonist.The disclosure of the publication of quoting in this specification sheets mode is by reference integrated with among this paper.
An object of the present invention is to provide other adjusting, particularly suppress the compound of c-Met.Have now found that formula as herein described (I) compound is the suppressor factor of c-Met, have multiple treatment and use.For example, formula (I) compound is suitable for treatment and depends on c-Met active disease, especially solid tumor or its transfer.Through suppressing c-Met, compound of the present invention also has the effectiveness as anti-inflammatory agent, for example is used to treat owing to infect the inflammatory conditions that causes.
Preferably, compound of the present invention is a metabolic stability, has favourable pharmacokinetics character, is nontoxic, and demonstrates spinoff seldom.In addition, preferred compound of the present invention exists with stable, physical form nonhygroscopic and easy preparation.A preferred aspect of the present invention relates to formula (I) compound, and it has the activity more excellent than the compound of prior art.Another preferred aspect of the present invention relates to formula (I) compound, and it has good kinases selectivity.
The present invention relates to compound or its pharmacy acceptable salt of formula (I):
Figure BDA0000151397020000021
Wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring;
Condition be when X be CH and B when being N, ring A is ring Ai or ring Aii;
Figure BDA0000151397020000022
When X is N and B when being N, ring A is Aiii;
Figure BDA0000151397020000031
And when X be that N and B are that N or X are N and B when being CH, ring A is Ai;
Figure BDA0000151397020000032
R 1Be the group that is selected from i, ii and iii:
Figure BDA0000151397020000033
R wherein 5It is heteroaryl 1
R 6Be hydrogen, deuterium, OH, methyl or halogen;
R 7Be hydrogen, deuterium, halogen or (C 1-C 3) alkyl, wherein said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen;
Perhaps R 6And R 7Form cyclopropyl with the carbon that they connected, wherein said cyclopropyl is optional to be replaced by methyl;
N is 0,1 or 2;
R 2Be hydrogen, NH 2Or (C 1-C 4) alkyl, wherein said (C 1-C 4) alkyl is optional by one or more OH, NH of being independently selected from 2Replace with the substituting group of halogen;
R 3Be hydrogen ,-CONH 2,-CONH (C 1-C 4) alkyl ,-the CONH phenyl, the phenyl in the wherein said CONH phenyl optional by one or more halogens ,-(C 1-C 4) alkyl ,-CO (C 1-C 4) alkyl ,-CO 2(C 1-C 4) alkyl, phenyl, heteroaryl 2,-CO heteroaryl 2,-CSNH 2,-CSNH (C 1-C 4) alkyl ,-the CSNH benzyl ,-SO 2(C 1-C 4) alkyl or-COCH 2Heterocyclic radical 1Replace said heterocyclic radical 1Optional by (C 1-C 3) the alkyl replacement;
R 4Be hydrogen or (C 1-C 3) alkyl;
Perhaps R 3And R 4Form 5 or 6 yuan the saturated or undersaturated monocyclic groups of part with the nitrogen that they connected, said monocyclic groups comprises 1 ring N atom, R 3And R 4Be connected with this N atom, said monocyclic groups is optional to comprise 1 other ring hetero atom that is independently selected from N, O and S, wherein said monocyclic groups by one or two=the O substituting group replaces.
Unless otherwise prescribed, otherwise should be suitable for following generic definition in this manual:
" compound of the present invention " or " multiple compound of the present invention " or " a kind of compound of the present invention " mean one or more formulas as herein described (I) compound.
Implication use that term used herein " comprises ", " containing " and " comprising " opened with it in this article, nonrestrictive.
Under the situation of using plural number (the for example plural number of compound, salt), this also comprises odd number (for example single compound, single salt)." a kind of compound " do not got rid of and had (for example in pharmaceutical prepn) more than one formula (I) compound (or its salt).
" treatment " comprises preventative (precaution) of disease, obstacle or illness and the progress of curative treatment and delay disease, obstacle or illness.
Any group that contains acyclic carbon with an above carbon atom or atomic group (moiety) be straight chain or side chain." alkyl " is meant alkyl straight chain or side chain.For example, (C 1-C 4) alkyl comprises methyl, ethyl, n-propyl or sec.-propyl and normal-butyl, isobutyl-, sec.-butyl or the tertiary butyl.
" heteroaryl 1" meaning the 9-that comprises 1,2,3 or 4 ring hetero atom that is independently selected from N, O and S or the undersaturated or undersaturated bicyclic groups of part of 10-unit, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1.
Heteroaryl 1Optional by one or more substituting groups, preferred 1,2 or 3 substituting group replacement, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, wherein said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen.
Heteroaryl 1Specific examples include but not limited to quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridine base, 1,6-phthalazinyl, 1; 7-phthalazinyl, 1,8-phthalazinyl, 2,6-phthalazinyl, 2; 7-phthalazinyl, pyrido [3,2-d] pyrimidyl, pyrido [4,3-d] pyrimidyl, pyrido [3; 4-d] pyrimidyl, pyrido [2,3-d] pyrimidyl, pyrido [2,3-b] pyrazinyl, pyrido [3; 4-b] pyrazinyl, Mi Dingbing [5; 4-d] pyrimidyl, pyrazine also [2,3-b] pyrazinyl, Mi Dingbing [4,5-d] pyrimidyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzo
Figure BDA0000151397020000051
Azoles base, indazolyl, benzotriazole base, pyrrolo-[2,3-b] pyridyl, pyrrolo-[2,3-c] pyridyl, pyrrolo-[3; 2-c] pyridyl, pyrrolo-[3,2-b] pyridyl, imidazo [4,5-b] pyridyl, imidazo [4; 5-c] pyridyl, pyrazolo [4,3-d] pyridyl, pyrazolo [4,3-c] pyridyl, pyrazolo [3; 4-c] pyridyl, pyrazolo [3,4-b] pyridyl, pseudoindoyl, indazolyl, purine radicals, pyrrocoline base, imidazo [1,2-a] pyridyl, imidazo [1; 5-a] pyridyl, pyrazolo [1,5-a] pyridyl, pyrrolo-[1,2-b] pyridazinyl and imidazo [1; 2-c] pyrimidyl, with and the counterpart of fractional saturation.
" heteroaryl 2" meaning undersaturated or the undersaturated monocycle of part or the bicyclic groups of 5-to the 10-unit that comprises 1,2,3 or 4 ring hetero atom that is independently selected from N, O and S, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1.Heteroaryl 2Optional by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, wherein said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen.Heteroaryl 2Specific examples include but not limited to pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, different
Figure BDA0000151397020000052
The azoles base, Azoles base, isothiazolyl, thiazolyl, 1,2,3-triazoles base, 1,3; 4-triazolyl, 1-oxa--2,3-di azoly, 1-oxa--2,4-di azoly, 1-oxa--2,5-di azoly, 1-oxa--3; 4-di azoly, 1-thia-2,3-di azoly, 1-thia-2,4-di azoly, 1-thia-2,5-di azoly, 1-thia-3; 4-di azoly, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, cinnolines base, quinazolyl, quinoxalinyl, azepine quinoxalinyl (azaquinazolinyl), phthalazinyl, naphthyridine base, 1,6-phthalazinyl, 1,7-phthalazinyl, 1; 8-phthalazinyl, 2,6-phthalazinyl, 2,7-phthalazinyl, pyrido [3; 2-d] pyrimidyl, pyrido [4,3-d] pyrimidyl, pyrido [3,4-d] pyrimidyl, pyrido [2; 3-d] pyrimidyl, pyrido [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl, Mi Dingbing [5; 4-d] pyrimidyl, pyrazine also [2,3-b] pyrazinyl, Mi Dingbing [4,5-d] pyrimidyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzo
Figure BDA0000151397020000054
Azoles base, indazolyl, benzotriazole base, pyrrolo-[2,3-b] pyridyl, pyrrolo-[2,3-c] pyridyl, pyrrolo-[3,2-c] pyridyl, pyrrolo-[3,2-b] pyridyl, imidazo [4; 5-b] pyridyl, imidazo [4,5-c] pyridyl, pyrazolo [4,3-d] pyridyl, pyrazolo [4,3-c] pyridyl, pyrazolo [3,4-c] pyridyl, pyrazolo [3; 4-b] pyridyl, pseudoindoyl, indazolyl, purine radicals, pyrrocoline base, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, pyrazolo [1,5-a] pyridyl, pyrrolo-[1; 2-b] pyridazinyl and imidazo [1,2-c] pyrimidyl, and the cyclic group of fractional saturation, as 3; 4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3; 4-tetrahydro pyridyl and 1,2,5, the 6-tetrahydro pyridyl.
" heterocyclic radical 1, " mean the saturated or undersaturated monocyclic groups of part of 5 or 6 yuan of comprising 1 or 2 ring hetero atom that is independently selected from N, O and S.Heterocyclic radical 1Specific examples include but not limited to 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1; 2,3,4-tetrahydro pyridyl and 1; 2; 5,6-tetrahydro pyridyl, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, piperidyl, 1,4-two Alkyl, 1, and 4-oxathiane base (1,4-oxathianyl), morpholinyl, 1,4-dithiane base, piperazinyl and 1,4-nitrogen thia cyclohexyl (1,4-azathianyl).
" heteroaryl 3, " mean the undersaturated or undersaturated bicyclic groups of part that comprises 1 or 2 the ring heteroatomic 9-of N or 10-unit.Heteroaryl 3Optional by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, wherein said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen.Heteroaryl 3Specific examples include but not limited to quinolyl, isoquinolyl, cinnolines base, azepine quinazolyl, quinoxalinyl, phthalazinyl, naphthyridine base, 1,6-phthalazinyl, 1; 7-phthalazinyl, 1,8-phthalazinyl, 2,6-phthalazinyl, 2; 7-phthalazinyl, indyl, benzimidazolyl-, indazolyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[2,3-c] pyridyl, pyrrolo-[3; 2-c] pyridyl, pyrrolo-[3; 2-b] pyridyl, pseudoindoyl, indazolyl, indolininyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, pyrazolo [1; 5-a] pyridyl and pyrrolo-[1,2-b] pyridazinyl.
Heteroaryl 4Mean and comprise 1,2,3 or 4 undersaturated monocyclic groups of undersaturated or part of 5 or 6 yuan that is independently selected from the ring hetero atom of N, O and S, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1.Heteroaryl 4Specific examples include but not limited to pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, different The azoles base,
Figure BDA0000151397020000063
Azoles base, isothiazolyl, thiazolyl, 1,2,3-triazoles base, 1,3,4-triazolyl, 1-oxa--2; 3-di azoly, 1-oxa--2,4-di azoly, 1-oxa--2,5-di azoly, 1-oxa--3,4-di azoly, 1-thia-2; 3-di azoly, 1-thia-2,4-di azoly, 1-thia-2,5-di azoly, 1-thia-3,4-di azoly, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 3; 4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1,2,3; 4-tetrahydro pyridyl and 1,2,5, the 6-tetrahydro pyridyl.
In a preferred embodiment, heteroaryl 4Mean and comprise 1 or 2 heteroatomic 5 or 6 yuan undersaturated monocyclic groups of ring N.The specific examples of this preferred embodiment includes but not limited to pyrryl, pyrazolyl, imidazolyl, pyridyl, pyridazinyl, pyrimidyl and pyrazinyl.
" disease " used herein comprises obstacle or illness.
In light of the disclosure herein, formula (I) compound is selected from any in the structure (Ia) to (Ie):
Figure BDA0000151397020000071
In one embodiment of the invention, the compound of formula (I) is provided, wherein
B is N;
Y is C or N;
X is CH or N;
Condition is when X is CH, and ring A is ring Ai or ring Aii;
When X was N, ring A was Aiii;
Figure BDA0000151397020000081
And when X be N and B when being CH, ring A is Ai.
Figure BDA0000151397020000082
Said compound has structure disclosed herein (Ia), (Ib), (Ic) or (Ie).
In another embodiment of the invention, the compound of formula (I) is provided, wherein
B is N;
Y is C or N;
X is CH or N;
Condition is when X is CH, and ring A is ring Ai or ring Aii;
Figure BDA0000151397020000083
And when X was N, ring A was Aiii;
Figure BDA0000151397020000084
Said compound has structure disclosed herein (Ia), (Ib) or (Ic).
In another embodiment of the invention, R 1Be i or ii:
Figure BDA0000151397020000091
In an embodiment preferred of the present invention, R 1Be i:
In another embodiment of the invention, R 1Be the group that is selected from i, ii and iii:
Figure BDA0000151397020000093
And R 5It is heteroaryl 3
In another embodiment preferred of the present invention, R 1Be i:
And R 5It is heteroaryl 3
In another embodiment of the invention, heteroaryl 1And heteroaryl 3Optional separately by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl.Especially, heteroaryl 1And heteroaryl 3Replaced by 1,2 or 3 substituting group independently of one another, said substituting group is independently selected from halogen and (C 1-C 2) alkyl.
In an embodiment preferred of the present invention, R 5Be indazolyl or quinolyl, it is optional by one or more halogen and (C of being independently selected from 1-C 3) substituting group of alkyl replaces.Especially, R 5Be indazolyl or quinolyl, it is chosen wantonly and is independently selected from halogen and (C by 1,2 or 3 1-C 3) substituting group of alkyl replaces.
In a further preferred embodiment of the present invention, R 5Be indazolyl, it is optional by 1,2 or 3 the substituting group replacement that is independently selected from methyl and fluorine, perhaps R 5Be quinolyl, it is optional by 1 or 2 fluoro substituents replacement.
In a specific embodiment of the present invention, R 5Be indazole-5-base, it is replaced by the methyl substituting group on 1, and optional further by 1 or 2 fluoro substituents replacement, perhaps R 5Be quinoline-6-base, it is optional by 1 or 2 fluoro substituents replacement.
In another embodiment of the invention, R 6Be hydrogen, deuterium, OH or halogen, particularly hydrogen, deuterium or halogen, in a preferred embodiment, R 6Be hydrogen.
In another embodiment of the invention, R 7Be hydrogen, deuterium, halogen or methyl, wherein said methyl is optional to be replaced by one or more substituting groups that are independently selected from OH and halogen.In another embodiment of the invention, R 7Be hydrogen, deuterium, halogen or methyl.In a preferred embodiment, R 7Be hydrogen.
Work as R 1Be i and R 6And R 7When not all being hydrogen, formula (I) compound is at R 1On contain unsymmetrical carbon.Comprise within the scope of the invention and contain R 1(R) enantiomorph of i or (S) formula of enantiomorph (I) compound or its mixture.In an embodiment preferred of the present invention, provide and contained R 1Formula (I) compound of (S) enantiomorph of i or comprise the mixture of (S) enantiomorph as main ingredient.
Figure BDA0000151397020000101
In another embodiment of the invention, R 1Be selected from the fluorine quinolyl methyl-, fluorine quinolyl methyl-d-, fluorine quinolyl methyl-d2-, quinolyl methyl-, the difluoro-quinoline ylmethyl-, fluorine quinolyl hydroxymethyl-, the quinolyl hydroxymethyl-, difluoro-quinoline base hydroxymethyl-, fluorine quinolyl hydroxyethyl-, the quinolyl hydroxyethyl-, fluorine quinolyl ethyl-, the quinolyl ethyl-, 4; 6-two fluoro-1-methylindazole base ethyls-, 4,6-two fluoro-1-methylindazole ylmethyls-, difluoro (quinolyl) methyl-, the quinolyl propyl-, difluoro-quinoline base ethyl-, the quinolyl cyclopropyl-, 6-fluoro-1-methyl-indazolyl ethyl-, 6-fluoro-1-methyl-indazolyl methyl-, 1-methylindazole ylmethyl-and 1-methylindazole base ethyl-.
In an embodiment preferred of the present invention, n is 0.
In another embodiment of the invention, R 2Be hydrogen or methyl.Preferably, R 2It is methyl.
In another embodiment of the invention, R 3Be hydrogen ,-CONH 2,-CONHCH 3,-CONH phenyl, the phenyl in the wherein said CONH phenyl optional by one or more halogens ,-(C 1-C 4) alkyl ,-COCH 3,-CO 2CH 3, phenyl, benzo
Figure BDA0000151397020000102
Azoles base, heteroaryl 4,-CO heteroaryl 4,-CSNH 2,-CSNH (C 1-C 2) alkyl ,-the CSNH benzyl ,-SO 2Me ,-COCH 2Morpholinyl, COCH 2Piperidyl or-COCH 2Piperazinyl replaces, and said piperazinyl is optional by one or more (C 1-C 3) the alkyl replacement;
In a further embodiment of the present invention, R 3Be hydrogen ,-CONH 2,-CONHCH 3,-CONH phenyl, the phenyl in the wherein said CONH phenyl optional by one or more halogens ,-(C 1-C 4) alkyl ,-COCH 3,-CO 2CH 3, phenyl, pyridyl, benzo
Figure BDA0000151397020000111
The azoles base ,-the CO pyridyl ,-CSNH 2,-CSNH (C 1-C 2) alkyl ,-the CSNH benzyl ,-SO 2Me ,-COCH 2Morpholine or-COCH 2Piperazine replaces, and is wherein said-COCH 2Piperazine in the piperazine is chosen wantonly on 4 and is replaced by methyl;
In an embodiment preferred of the present invention, R 3Be-CONH 2
In another embodiment preferred of the present invention, R 4Be hydrogen or methyl, be more preferably hydrogen.
In the embodiment of a confession alternative of the present invention, R 3And R 4Nitrogen with they connected forms
Figure BDA0000151397020000112
Oxazolidone,
Figure BDA0000151397020000113
Oxazolidinedione, imidazolidone or imidazolidimedione.
Halogen means fluorine, chlorine, bromine or iodine.In a specific embodiment of the present invention, halogen is a fluorine or chlorine.Preferably, halogen is a fluorine.
The present invention relates to the compound of formula (I),
Figure BDA0000151397020000114
Wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring;
Condition be when X be CH and B when being N, ring A is ring Ai or ring Aii;
Figure BDA0000151397020000121
When X is N and B when being N, ring A is Aiii;
Figure BDA0000151397020000122
And when X be that N and B are that N or X are N and B when being CH, ring A is Ai;
Figure BDA0000151397020000123
R 1Be the fluorine quinolyl methyl-, fluorine quinolyl methyl-d-, fluorine quinolyl methyl-d2-, quinolyl methyl-, the difluoro-quinoline ylmethyl-, fluorine quinolyl hydroxymethyl-, the quinolyl hydroxymethyl-, difluoro-quinoline base hydroxymethyl-, fluorine quinolyl hydroxyethyl-, the quinolyl hydroxyethyl-, fluorine quinolyl ethyl-, the quinolyl ethyl-, 4; 6-two fluoro-1-methylindazole base ethyls-, 4,6-two fluoro-1-methylindazole ylmethyls-, difluoro (quinolyl) methyl-, the quinolyl propyl-, difluoro-quinoline base ethyl-, the quinolyl cyclopropyl-, 6-fluoro-1-methyl-indazolyl ethyl-, 6-fluoro-1-methyl-indazolyl methyl-, 1-methylindazole ylmethyl-or 1-methylindazole base ethyl-;
R 2Be hydrogen, NH 2, ethyl or methyl;
R 3Be-CONH 2, ethyl ,-CO (C 1-C 2) alkyl, phenyl, pyridyl ,-the CONH phenyl ,-CONH chloro-phenyl-, CONHCH 3, benzo
Figure BDA0000151397020000124
The azoles base ,-SO 2Me, CSNH (C 1-C 2) alkyl, CSNH benzyl-,-CSNH 2,-COCH 2Morpholine ,-COCH 2(4-N-METHYL PIPERAZINE), hydrogen ,-CO 2CH 3Or-the CO pyridyl,
R 4Be hydrogen or methyl;
Perhaps R 3And R 4Nitrogen with they connected forms
Figure BDA0000151397020000131
Oxazolidone,
Figure BDA0000151397020000132
Oxazolidinedione, imidazolidone or imidazolidimedione.
In a preferred embodiment of the present invention, the compound of formula (I) is provided, wherein B is N;
Y is C or N;
X is CH or N;
Condition is when X is CH, and ring A is ring Ai or ring Aii;
And when X was N, ring A was Aiii;
R 1Be i;
Figure BDA0000151397020000135
R 5Be quinolyl, it is optional by 1 or 2 fluoro substituents replacement;
R 2It is methyl;
R 3Be-CONH 2
R 4Be hydrogen;
And
R 6And R 7All be hydrogen;
R 6And R 7All are fluorine;
R 6And R 7All are deuteriums; Perhaps
R 6Be methyl and R 7Be hydrogen, to form the S-enantiomorph.
Multiple embodiments of the present invention is as described herein.Should be appreciated that, in each embodiment given characteristic can with other given characteristics combination, thereby other embodiment is provided.
In a specific embodiment, the invention provides one or more compounds that are selected from embodiment compound disclosed herein or its pharmacy acceptable salt.
Term used herein " isomer " but be meant the arrangement different compounds different with configuration with identical molecular formula atom.In addition, term used herein " optically active isomer " or " steric isomer " are meant any one in the various stereoisomerism configurations that given compound of the present invention can exist, and comprise geometrical isomer.Should be understood that substituting group can be connected on the chiral centre of carbon atom.Therefore, the present invention includes enantiomorph, diastereomer or the racemoid of compound." enantiomorph " is a pair of steric isomer of stackable mirror image not each other.1: 1 mixture of a pair of enantiomorph is " racemize " mixture.Under suitable situation, this term is used to represent racemic mixture." diastereomer " be have at least two asymmetric atoms, but the steric isomer of mirror image each other not.The absolute stereo chemistry provides according to Cahn-lngold-Prelog R-S system.When a kind of compound was pure enantiomorph, the stereochemistry on each chiral carbon can provide with R or S.The not clear compound of its absolute configuration that splits can be represented as (+) or (-) according to they rotate plane polarized light under the sodium D-line wavelength direction (dextrorotation or left-handed).Some compound as herein described contains one or more asymmetric centers or axle, therefore can produce enantiomorph, diastereomer and can chemically be defined as at absolute stereo (R)-or (S)-other stereoisomeric forms in any ratio.The present invention includes the possible isomer of all these types, comprise racemic mixture, optically pure form and intermediate mixture.(R) of optically active-with (S)-isomer can or split with routine techniques with the preparation of chiral synthon or chiral reagent.If compound contains two keys, then substituting group can be E or Z configuration.If compound contains dibasic naphthenic base, then naphthenic substituent can have cis-or trans-configuration.Also comprise all tautomeric forms.
Any asymmetric atom in the compound of the present invention (for example carbon etc.) can with racemize or enantiomorph enrichment, for example (R)-, (S)-or (R, S)-configuration exists, for example for may reside in R defined herein 1Unsymmetrical carbon in the group (i).In certain embodiments, each asymmetric atom has (R) of at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess or at least 99% enantiomeric excess-or (S)-configuration.Preferably, for asymmetric R defined herein 1Group (i), (S) enantiomorph is excessive with amount recited above.
If possible, the substituting group that has on the atom of unsaturated link(age) can exist with cis-(Z)-or trans-(E)-form.Preferably, hydrazone of the present invention have trans-(E)-form.
Therefore; Compound of the present invention used herein can be any one form in possible isomer, rotational isomer, atropisomer, tautomer or its mixture, for example is the form of pure basically geometrical isomer (cis or trans-isomer(ide)), diastereomer, optically active isomer (enantiomorph), racemoid or its mixture.
The isomer mixture of any gained all can split into pure or pure basically geometrical isomer or optically active isomer, diastereomer, racemoid according to the physics and chemistry difference of component, for example splits through chromatography and/or fractionation crystallization.
The end product of any gained or the racemoid of midbody all can split into optically active enantiomorph through currently known methods, for example split through separating with the acid of optically active or its diastereoisomeric salt that alkali obtained and the acidity or the basic cpd of release optically active.Therefore; Particularly; Can utilize basic group compound of the present invention to be split into their optically active enantiomorph; For example tartrate, dibenzoyl tartaric acid, diacetylated tartrates, two-O of the acid through fractional crystallization and optically active for example, the salt of O '-right-toluyl tartrate, racemic melic acid, oxysuccinic acid or camphor-10-sulfonic acid formation splits.Also can pass through chiral chromatography, for example HPLC (HPLC) with chiral sorbent resolution of racemic product.
The given any structure formula of this paper is also all represented the form that does not provide and the isotope-labeled form of said compound.Isotope-labeled compound has the structure that the given structural formula of this paper is described, and is replaced but one or more atoms have the atom of selected atomic mass or total mass number.Can mix the isotropic substance that isotopic instance in the compound of the present invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example be respectively 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 125I.Various isotope-labeled compounds of the present invention, for example mixed ri as 3H, 13C with 14Those of C.Said isotope-labeled compound can be used on metabolism research and (preferably uses 14The C mark), reaction kinetics research (is for example used 2H or 3The H mark), detection or imaging technique [like positron emission fault Imaging (PET) or single photon emission computed tomography Imaging (SPECT), comprise in medicine or the substrate tissue distribution assay method or are used in patient's the radiation treatment.Especially, 18The compound of F or mark can be particularly preferred for PET or SPECT research.In addition, use heavier isotropic substance such as deuterium (promptly 2H) replacement can obtain some treatment advantage, and said treatment advantage is because higher metabolic stability causes, and for example the transformation period increases or the dose requirements reduction in the body.Isotope-labeled compound of the present invention and its prodrug generally can carry out that disclosed operation prepares in schema or embodiment and the preparation example hereinafter described through replace nonisotopically labelled reagent with the isotope-labeled reagent that obtains easily.
In addition, (promptly with heavier isotropic substance, particularly deuterium 2H or D) replace and can obtain some treatment advantage, said treatment advantage is because higher metabolic stability causes, for example the transformation period increases or dose requirements reduces or therapeutic index is improved in the body.Should be understood that the deuterium in this context is regarded as the substituting group of formula (I) compound.The concentration of said heavier isotropic substance, particularly deuterium can define through the isotopic enrichment factor.Term used herein " the isotopic enrichment factor " means the ratio of isotopic abundance and said natural abundance of isotopes.If the substituting group in the compound of the present invention is the deuterium that provides, then said compound has the isotopic enrichment factor of at least 3500 (mixing 52.5% deuterium at each specified D atom place), at least 4000 (mixing 60% deuterium), at least 4500 (mixing 67.5% deuterium), at least 5000 (mixing 75% deuterium), at least 5500 (mixing 82.5% deuterium), at least 6000 (mixing 90% deuterium), at least 6333.3 (mixing 95% deuterium), at least 6466.7 (mixing 97% deuterium), at least 6600 (mixing 99% deuterium) or at least 6633.3 (mixing 99.5% deuterium) as far as each specified D atom.In compound of the present invention, specifically be not indicated as being any stable isotope of any this atom of atom represent of specific isotope.Except as otherwise noted, otherwise when a position specifically was indicated as being " H " or " hydrogen ", this position was appreciated that the hydrogen with natural abundance isotopics.Therefore, in compound of the present invention, any atom represent deuterium that specifically is indicated as being deuterium (D), the for example deuterium of the given scope of preceding text.
Isotope-labeled formula (I) compound generally can known by one of skill in the art routine techniques or through with the embodiment of having with prepare the similar method of the method described in the example and replaces previously used cold reagent to prepare with the isotope-labeled reagent that suits.
Term used herein " pharmacy acceptable salt " is meant the biological effectiveness that kept compound of the present invention and character and the salt that does not have undesirable character in biology or others usually.Said salt can perhaps exist with the form of mixtures with free formula (I) compound by exist singly.In many cases, because the existence of amino or group similar with it, compound of the present invention can form acid salt.
Pharmaceutically-acceptable acid addition can use mineral acid and organic acid to form, for example acetate, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, hydrosulfate/vitriol, camsilate (camphorsulfornate), muriate/hydrochloride, chloro theophylline salt (chlortheophyllonate), Citrate trianion, ethanedisulphonate, fumarate, gluceptate, glyconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactic acid salt, Lactobionate, dodecyl sulfate, malate, PHENRAMINE MALEATE, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate salt, octadecane hydrochlorate, oleate, oxalate, palmitate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, Polygalacturonate, propionic salt, stearate, SUMATRIPTAN SUCCINATE, sulfosalicylate, tartrate, tosylate and trifluoroacetate.Can comprise for example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc. by its mineral acid that obtains salt of deriving.Can comprise for example acetate, propionic acid, oxyacetic acid, oxalic acid, toxilic acid, propanedioic acid, succsinic acid, fumaric acid, tartrate, Hydrocerol A, phenylformic acid, racemic melic acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, sulphosalicylic acid etc. by its organic acid that obtains salt of deriving.
Pharmacy acceptable salt of the present invention can be synthetic by parent compound, acid or alkali atom group through the conventional chemical method.Generally speaking, said salt can prepare through free alkali form and the stoichiometric suitable acid-respons that makes these compounds.Said reaction is carried out in the mixture of the two in water or in organic solvent or at this usually.Generally speaking, under feasible situation, it is desirable using non-water vehicle such as ether, ETHYLE ACETATE, ethanol, Virahol or acetonitrile.The tabulation of suitable salt in addition for example is found in " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985); " Handbook of Pharmaceutical Salts:Properties, Selection, and Use ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002)." salt " or " its salt " can perhaps exist with the form of mixtures with free formula (I) compound by exist singly.
For the isolated or purified purpose, also can use pharmaceutically unacceptable salt, for example picrate or perchlorate.For therepic use, only can use pharmacy acceptable salt or free cpds (wherein can use), so they are preferred with the form of pharmaceutical prepn.In view of the substantial connection between the new compound of free form and their salt form (comprise can be used as midbody, for example in the purifying of new compound or evaluation, be used as those salt of midbody); If suitable and favourable, preceding text and hereinafter are any to be to be understood that to also having mentioned corresponding salt mentioning of free cpds.
Compound of the present invention both can exist with the form of non-solventization, also can exist with the form of solvation.Term ' solvate ' is used in this article describing and comprises for example alcoholic acid molecular complex of compound of the present invention and one or more pharmaceutically acceptable solvent molecule.When said solvent was water, ' hydrate ' used a technical term.Pharmaceutically acceptable solvate comprises hydrate and other solvate, and wherein recrystallisation solvent can be that to have carried out isotropic substance substituted, for example D 2O, d 6-acetone, d 6-DMSO.The given any structure formula of this paper is represented hydrate, solvate and the polymorphic form of said compound and their mixture.
Containing can be as the compound of the present invention of the group of hydrogen bond donor and/or acceptor, be that formula (I) compound can form thing (co-crystal former) and forms eutectic (co-crystal) with suitable eutectic.These eutectics can form operation by formula (I) compound through known eutectic.Said operation comprises grinding, heating, is total to distillation, congruent meltingization or makes the eutectic that the brilliant together formation thing of formula (I) compound contacts and separation forms thus under crystallization condition in solution.Suitable eutectic formation thing comprises those described in the WO 2004/078163.Therefore, the present invention also comprises the eutectic that comprises formula (I) compound.
Therefore, compound of the present invention comprises formula I compound defined herein, its polymorphic form and isomer (comprising optically active isomer, geometrical isomer and tautomer) and isotope-labeled formula I compound.Embodiment preferred (its be independently, the venue or with the mode of any combination or inferior combination by preferred) in, the present invention relates to formula (I) compound of free alkali form or acid salt form, substituting group wherein such as defined herein.
Compound of the present invention can be with the prodrug administered.Some verivate of formula (I) compound that therefore, itself can have very little pharmacologically active or not have a pharmacologically active can be converted in being administered to health or on the health time, for example be converted to through hydrolytic rupture and have required active formula (I) compound.Said verivate is called as ' prodrug '.[the other data about the use of prodrug can find in serial document: ' Pro-drugs as Novel Delivery Systems; Vol.14; ACS Symposium Series (T Higuchi and W Stella) and ' Bioreversible Carriers in Drug Design '; Pergamon Press, 1987 (editor E B Roche, American Pharmaceutical Association).]
Prodrug can be for example through preparing with the suitable functional group that exists in ' preceding atomic group (pro-moiety) ' replacement formula (I) compound described in some atomic group well known by persons skilled in the art, for example HBundgaard " Design of Prodrugs " (Elsevier, 1985).
Some instances of said prodrug comprise:
(i) (under situation COOH), its ester for example, is used (C to contain carboxyl functional group at formula (I) compound 1-C 8) alkyl replacement hydrogen;
(under situation OH), its ether for example, is used (C (ii) to contain alcohol functional group at formula (I) compound 1-C 6) alkyloyl oxygen ylmethyl replacement hydrogen; With
(iii) contain uncle or the (NH of secondary amino group functional group at formula (I) compound 2Or-NHR, wherein under the situation of R ≠ H), its acid amides, for example, with (C 1-C 10) one or two hydrogen of alkyloyl replacement.
Some formula (I) compound itself also can be as the prodrug of other formula (I) compound.
The invention still further relates to the pharmaceutically acceptable prodrug of formula (I) compound.The invention still further relates to the pharmaceutically acceptable metabolite of formula (I) compound.
" disease that C-Met is tyrosine kinase mediated " especially with useful mode to the arrestin Tyrosylprotein kinase, especially suppress the c-Met kinases have response (for example improve one or more symptoms, postpone disease outbreak, realize the temporary healing of disease or cure fully) those obstacles.These obstacles comprise proliferative disease such as tumor disease; Solid tumor particularly; And transfer, for example heredity Papillary Renal Cell Carcinoma (PRCC), the sporadic form of PRCC, head and neck cancer, squamous cell carcinoma, cancer of the stomach, carcinoma of the pancreas, lung cancer, bladder cancer, breast cancer, leiomyosarcoma, glioblastoma, melanoma, alveolar soft part sarcoma.These obstacles also comprise inflammatory conditions, like the inflammatory conditions that causes owing to infection.
" combination " is meant the fixed combination of a dosage unit form or is used for the cover medicine box of combined administration (akit of parts); Its Chinese style (I) compound and COMBINATION OF THE INVENTION (a kind of other medicines for example described below; Be also referred to as " therapeutical agent " or " concomitant medication ") can use independently or in time interval, use respectively in the identical time, especially make COMBINATION OF THE INVENTION show under the for example synergistic situation of effect of cooperation at these time intervals.Term used herein " is used " jointly or " combination use " etc. comprises selected COMBINATION OF THE INVENTION is applied to the single individuality (for example patient) that needs it, and comprises the regimen that each medicine wherein must not used or use in the identical time through identical route of administration.Term used herein " drug regimen " means the product that mixes or combine to obtain through with more than one activeconstituentss, and comprises the fixed combination and the on-fixed combination of activeconstituents.Term " fixed combination " means activeconstituents, and for example formula (I) compound and COMBINATION OF THE INVENTION all are applied to the patient simultaneously with the form of single entity or dosage.Term " on-fixed combination " mean activeconstituents for example formula (I) compound and COMBINATION OF THE INVENTION with the entity that separates simultaneously, parallel (concurrently) or (do not have concrete time limitation) in succession and be applied to the patient, the treatment level of significance of two kinds of compounds is provided in the wherein said patient's of being applied in body.The latter also is applicable to HAART (cocktail therapy), for example uses three kinds or more kinds of activeconstituents.
Formula (I) compound and the wherein said preparation method that the invention particularly relates among the embodiment to be provided.
Like preceding text with hereinafter described, formula (I) compound has valuable pharmacological character.
In another embodiment of the invention, the treatment obstacle relevant with c-Met or the method for illness are provided.Obstacle to be treated or illness be proliferative disease such as cancer or inflammatory conditions preferably.Formula (I) compound also can be used for treating the diseases related of the illness relevant with c-Met.
A: proliferative disease: formula (I) compound is particularly useful for treating one or more in the following proliferative disease:
Formula (I) compound can be used for treating cancer; Wherein said cancer is selected from the cancer of the brain, cancer of the stomach, reproductive system cancer, urinary system cancer, prostate cancer, bladder cancer (shallow table and muscle invasion and attack), breast cancer, cervical cancer, colorectal carcinoma, colorectal carcinoma, neurospongioma (comprise glioblastoma, a modification astrocytoma, prominent astrocytoma (oligoastrocytoma), Oligodendroglioma) less, the esophageal carcinoma, cancer of the stomach, gastrointestinal cancer, liver cancer, hepatocellular carcinoma (HCC) (the HCC Childhood of comprising), head and neck cancer (comprising neck squamous cell carcinoma, nasopharyngeal carcinoma), Hu Erteer cell carcinoma, epithelial cancer, skin carcinoma, melanoma (comprising malignant melanoma), mesothelioma, lymphoma, myelomatosis (comprising multiple myeloma), white blood disease, lung cancer (comprising nonsmall-cell lung cancer (comprise all histology hypotypes: gland cancer, squamous cell carcinoma, bronchioalveolar carcinoma, large cell carcinoma and squama gland mixed type (adenosquamous mixed type)), small cell lung cancer), ovarian cancer, carcinoma of the pancreas, prostate cancer, kidney (including but not limited to Papillary Renal Cell Carcinoma), intestinal cancer, renal cell carcinoma (comprises heredity and sporadic Papillary Renal Cell Carcinoma; I type and II type, and hyaline cell renal cell carcinoma); Sarcoma, particularly osteosarcoma, clear cell sarcoma (clear cell sarcoma) and soft tissue sarcoma's (comprising alveolar shape rhabdosarcoma and embryonal rhabdomyosarcoma, alveolar soft part sarcoma); Thyroid carcinoma (papillary thyroid carcinoma and other hypotype).
Formula (I) compound can be used for treating cancer, and wherein said cancer is cancer of the stomach, colorectal carcinoma, liver cancer, reproductive system cancer, urinary system cancer, melanoma or prostate cancer.In a specific embodiment, said cancer is the liver cancer or the esophageal carcinoma.
Formula (I) compound can be used for treating colorectal carcinoma, comprises transfer, the for example transfer in liver, and treatment nonsmall-cell lung cancer.
Formula (I) compound also can be used for treating heredity palilate kidney (hereditary papillary renal carcinoma) (Schmidt; L. wait the people; Nat.Genet.16,68-73,1997) and wherein c-MET cross and express or by sudden change (Jeffers and Vande Woude.Oncogene 18; 5120-5125,1999; And the reference of wherein being quoted) or chromosome rearrangement (TPR-MET for example; People such as Cooper, Nature 311,29-33,1984; Park. wait the people, Cell 45,895-904,1986) other proliferative disease of constitutively activate.
Formula (I) compound also can be used for treating that this paper provides or known in the art other cancer and illness.
B: inflammatory conditions: formula (I) compound is particularly suitable for treating one or more inflammatory conditions.
In a further embodiment, said inflammatory conditions causes owing to infecting.In one embodiment, treat-ment will be blocked pathogenic infection.In a specific embodiment, said infection is an infectation of bacteria, and for example Listera (Listeria) infects.Referring to people such as for example Shen, Cell 103:501-10, (2000), and wherein bacterium surface albumen is through combining to activate the c-Met kinases with the extracellular domain of acceptor, thus the effect of imitation cognate ligand HGF/SF.
Formula (I) compound also can be used for treating that this paper provides or other inflammatory disorder known in the art and illness.
C: combination treatment: in certain embodiments, any one in the aforesaid method comprises further uses chemotherapeutic drug.
In a related embodiment, said chemotherapeutic drug is an anticarcinogen.Run through the application specific combined is provided.
In an other related embodiment, any one in the aforesaid method comprises further uses the path specific inhibitor.Said path specific inhibitor can be a chemotherapeutic drug, perhaps can be biological medicine, for example antibody.The path specific inhibitor includes but not limited to the suppressor factor of EGFR, Her-2, Her-3, VEGFR, Ron, IGF-IR, PI-3K, mTOR, Raf.
In aforesaid method in several different methods other relevant embodiment, after being applied to individuality or exposing cell, these methods can further comprise the development of observing cancer or the improvement or the retardance of transfer.
Therefore, in one embodiment, the present invention relates to treat the obstacle relevant with c-Met or the method for illness, it comprises formula (I) compound of using significant quantity to its individuality of needs.
In an other embodiment, the present invention relates to formula (I) compound or its pharmacy acceptable salt, it uses with medicine type, especially for the tyrosine kinase mediated disease of one or more C-Met of treatment.
In an other embodiment, the present invention relates to formula (I) compound or its pharmacy acceptable salt purposes in the preparation medicament, said medicament is used to treat the tyrosine kinase mediated disease of one or more C-Met.
In an other embodiment; The present invention relates to treat has the disease of response or the method for obstacle to suppressing the C-Met Tyrosylprotein kinase; It comprises to the warm-blooded animal of the said treatment of needs uses formula (I) compound or its pharmacy acceptable salt, especially uses formula (I) compound or its pharmacy acceptable salt to resist the effective amount of said disease.
In an other embodiment, the present invention relates to pharmaceutical composition, it comprises formula (I) compound and at least a pharmaceutical carrier or thinner as activeconstituents.
In an other embodiment, the present invention relates to pharmaceutical composition, it comprises: (a) formula of significant quantity (I) compound and pharmacy acceptable salt thereof, pharmaceutically acceptable prodrug and/or the metabolite of pharmaceutical active is arranged; (b) one or more pharmaceutically acceptable vehicle and/or thinners.
In an other embodiment; The present invention relates to pharmaceutical composition; It is used to treat the disease of the warm-blooded animal that comprises the people; For example solid tumor or liquid tumors (liquid tumor), said pharmaceutical composition comprise formula mentioned above (I) compound of treating said disease effective dose or the pharmacy acceptable salt and the pharmaceutically acceptable carrier (=solid support material) of said compound.
In another embodiment of the invention; Pharmaceutical prepn (compsn) is provided; It comprises pharmacy acceptable salt or its hydrate or the solvate of formula defined herein (I) compound or said compound; And at least a pharmaceutically acceptable carrier and/or thinner, and optional one or more other therapeutical agents that comprises.
Term used herein " pharmaceutically acceptable carrier " comprises any solvent, (for example disperses vehicle, dressing, tensio-active agent, inhibitor, sanitas; Antibacterial agent, anti-mycotic agent), isotonic agent (isotonic agent), absorption delay agent, salt, sanitas, medicine, medicine stablizer, tackiness agent, vehicle, disintegrating agent, lubricant, sweeting agent, correctives, dyestuff etc. and combination thereof; As well known by persons skilled in the art (referring to for example Remington ' s Pharmaceutical Sciences; The 18th edition; Mack Printing Company, 1990, pp.1289-1329).Only if any conventional carrier is incompatible with activeconstituents, otherwise its application in therapeutic compsn or pharmaceutical composition is just included.
" the treatment significant quantity " of term compound of the present invention is the amount that causes the compound of the present invention of individual biology or medicinal response; Said response is reduction or inhibitory enzyme or protein-active for example; Perhaps improve symptom, alleviate illness, slow down or postpone the progress of disease, perhaps preventing disease etc.In a nonrestrictive embodiment, term " treatment significant quantity " be meant when being applied to individuality (1) effectively at least part alleviate, suppress, prevent and/or improve (i) by the cMet mediation or (ii) active relevant or be the amount of compound of the present invention of expression that illness or disease or obstacle or (2) of characteristic reduce or suppress activity or (3) minimizing or the inhibition cMet of cMet (iii) with the activity (normal or unusual) of cMet with cMet.In another nonrestrictive embodiment, term " treatment significant quantity " be meant when be applied to cell or tissue or non cellular organismo when learning material or substratum effectively at least part reduce or suppress the active of cMet or at least part reduce or suppress the amount of compound of the present invention of the expression of cMet.
Term used herein " individuality " is meant animal.Typically, said animal is a Mammals.Individuality also refers to for example primate (for example people), milk cow, sheep, goat, horse, dog, cat, rabbit, mouse, fish, bird etc.In certain embodiments, said individuality is a primate.In also having some embodiments, said individuality is the people.
Term used herein " inhibition " is meant and alleviates or suppress given illness, symptom or obstacle or disease that the baseline that perhaps significantly reduces BA or process is active.
Any disease of term used herein " treatment " or obstacle are meant in one embodiment and improve said disease or obstacle (that is, slow down or stop or reduce the development of disease or at least a its clinical symptom).In another embodiment, " treatment " is meant alleviation or improves at least a body parameter, comprise those body parameters that the patient can not distinguish.In also having the another one embodiment, " treatment " is meant and (for example stablizing recognizable symptom) on the health, on physiology, (for example stablizes body parameter) or aspect these two, regulating disease or obstacle.In also having the another one embodiment, " treatment " is meant prevention or postpones outbreak or the generation or the progress of disease or obstacle.
As employed at this paper, if said individuality will be biologically, medically or on quality of life from said treatment, benefiting, then individuality is " needs " treatment.
As employed at this paper; (especially in the context of claim) used singular references and similar terms are appreciated that and both comprise odd number in the context of the present invention; Also comprise plural number, this paper have in addition the explanation or context clearly have the phase antirepresentation except.
In yet another aspect, the invention provides pharmaceutical composition, it comprises compound of the present invention and pharmaceutically acceptable carrier.Said pharmaceutical composition can be used for specific route of administration by preparation, as Orally administered, parenteral is used and rectal administration etc.In addition, pharmaceutical composition of the present invention can be made into solid form (comprising capsule, tablet, pill, granule, powder or suppository without limitation) or liquid form (comprising solution, suspensoid or emulsion without limitation).Pharmaceutical composition can stand the conventional pharmaceutical operation as sterilizing and/or can containing conventional inert thinner, lubricant or buffer reagent and auxiliary agent (adjuvant), like sanitas, stablizer, wetting agent, emulsifying agent and buffer reagent etc.
Typically, pharmaceutical composition is tablet or gelatine capsule agent, its comprise activeconstituents and
A) thinner, for example lactose, Vadex, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycocoll;
B) lubricant, for example silicon-dioxide, talcum powder, Triple Pressed Stearic Acid, its magnesium salts or calcium salt, and/or polyoxyethylene glycol; For tablet, also have
C) tackiness agent, for example neusilin, starch paste, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine and/or Vinylpyrrolidone polymer; If desired, also have
D) disintegrating agent, for example starch, agar, Lalgine or its sodium salt or effervescent mixture; And/or
E) absorption agent, tinting material, correctives and sweeting agent.
Can be with tablet according to methods known in the art bag film-coat or enteric coated.
Be used for the compound of the present invention that Orally administered suitable compsn comprises the significant quantity of tablet, lozenge, water-based or oiliness suspensoid, dispersible powder or particle, emulsion, hard or soft capsule or syrup or elixir form.The compsn that is used to orally use is according to any method preparation that is used for pharmaceutical compositions known in the art, and said compsn can contain one or more and be selected from the material of sweeting agent, correctives, tinting material and sanitas so that pharmaceutically graceful and good to eat preparation are provided.Tablet can contain and be suitable for preparing the activeconstituents of the nontoxic pharmaceutically acceptable mixed with excipients of tablet.These vehicle are for example inert diluent such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation agent or disintegrating agent, for example W-Gum or Lalgine; Tackiness agent, for example starch, gelatin or gum arabic; And lubricant, for example Magnesium Stearate, Triple Pressed Stearic Acid or talcum powder.Thereby being the disintegration to postpone in gi tract no dressing or through the known technology dressing, tablet lasting effect is being provided with absorption and during growing.For example, the serviceable time postpones material such as Zerol or Stearic diglyceride.The preparation that is used to orally use can be for example lime carbonate, calcium phosphate or white bole blended hard gelatin capsule form or activeconstituents and water or the oily vehicle soft gelatin capsule form of peanut oil, whiteruss or mixed with olive oil for example wherein of activeconstituents and inert solid diluent wherein.
Some injectable compsn is to wait the aqueous solution or the aqueous suspension of opening, and suppository is prepared by lipomul or suspensoid expediently.Said compsn can and/or contain auxiliary agent by sterilization, like the salt and/or the buffer reagent of sanitas, stablizer, wetting agent or emulsifying agent, solution promotor, adjusting osmotic pressure.In addition, they also can contain upward valuable material of other treatment.Said compsn according to mixing, granulation or the coating method preparation of routine, contains and has an appointment 0.1-75% or contain the 1-50% activeconstituents of having an appointment respectively.
The suitable compsn that is used for the transdermal application comprises the compound of the present invention and the suitable carriers of significant quantity.The carrier that is suitable for transdermal delivery comprises that help is through acceptable solvent on the absorbable pharmacology of accepting main body skin.For example; Transdermal device is the form of bandage; It comprises back sheet, contain compound and optional carrier-containing storage storehouse, optional comprise go through prolongation during compound is delivered to the control speed barrier of accepting main body skin with control and predetermined rate delivery, and this device is fixed in the device of skin.
The suitable compsn that be used for topical application, for example is applied topically to skin and eye comprises the aqueous solution, suspensoid, ointment, ointment, gel or sprayable preparation (for example be used for send through aerosol sprayable preparation) etc.Said local delivery system is suitable for dermal application especially, for example is used to treat skin carcinoma, for example in sunscreen, lotion, sprays etc., is used for preventive use.Therefore they are particularly suitable for in the topical formulations known in the art (comprising cosmetic preparation).Said local delivery system can contain solubilizing agent, stablizer, tension force promotor (tonicity enhancing agent), buffer reagent and sanitas.
As used herein, topical application also can relate in suction or the nose to be used.They can be (independent with dry powder; Form of mixtures; For example with the dry mixture of lactose; Perhaps blended component particles is for example with the blended component particles of phosphatide) form is by in the Diskus or to send easily in container, pump, atomizer, spraying gun or the sprinker of aerosol spray form by pressurization, uses or do not use suitable propellent.
The invention still further relates to pharmaceutical composition; It comprises significant quantity, formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers of significant quantity in treatment one of above-mentioned disease, obstacle or illness especially; Said carrier is suitable for part, intestines interior (for example oral or rectum) or parenteral and uses, and can be inorganic or organic solid or liquid.
The dosage that is applied to the activeconstituents of warm-blooded animal depends on multiple factor, comprises patient's type, kind, age, body weight, sex and medical condition; The seriousness of illness to be treated; Route of administration; Patients " renal function and liver function; With employed particular compound.The doctor of common skill, clinician or animal doctor can easily confirm and open prevention, antagonism illness or stop illness to make progress needed medicine effective quantity.Reach and produce effect but scheme that the optimum precision of drug level in the avirulent scope need be the basis to the kinetics of target position degree capable of using with medicine.This comprises distribution, balance and the elimination of considering medicine.The warm-blooded animal that is applied to about 70kg body weight for example people's formula (I) compound or its pharmacy acceptable salt dosage preferably every day everyone about 3mg to about 5g, 10mg about 1.5g extremely more preferably from about; It preferably is divided into 1 to 3 single dose, and said single dose can for example have identical size.Usually, children accept the half the of grownup's dosage.
Pharmaceutical composition of the present invention or drug regimen can be the unitary doses of about one or more activeconstituentss of 1-1000mg that is used for the individuality of about 50-70kg, perhaps about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg or about 1-50mg activeconstituents.The treatment effective dose of compound, pharmaceutical composition or its combination depends on individual kind, body weight, age and individual state, obstacle or illness or its seriousness to be treated.The doctor of common skill, clinician or animal doctor can easily confirm the significant quantity of each activeconstituents that the progress of prevention, treatment obstacle or disease or inhibition obstacle or disease is required.
Above-mentioned dosage character can advantageously be used Mammals, and for example mouse, rat, dog, monkey or its organ, tissue and prepared product that exsomatizes prove in testing in vitro and in vivo.Compound of the present invention can with solution for example the aqueous solution the form in-vitro application and for example in the form intestines with the suspension or the aqueous solution, parenteral (advantageously, intravenously) uses.External dosage can be about 10 -3To 10 -9Volumetric molar concentration.The interior therapeutic significant quantity can be about 0.1-500mg/kg or about 1-100mg/kg, and is different and different according to route of administration.
In another embodiment of the invention, the combination of formula (I) compound and one or more other therapeutic activity agent is provided.Therefore; Formula (I) compound can use separately or with one or more other therapeutical agent combined administrations; Possible combination treatment is taked the form of fixed combination; Using of compound perhaps of the present invention and one or more other therapeutical agents staggered carried out or given independently of one another, perhaps combined administration fixed combination and one or more other therapeutical agents.
In addition or extraly, formula (I) compound can also carry out combined administration with chemotherapy, radiotherapy, immunotherapy, surgical intervention (surgical intervention) or these combination, in particular for oncotherapy.It also is possible in the situation of above-mentioned other therapeutic strategy, carrying out long-term treatment as assisting therapy.Other possible treatment is the treatment of behind tumor regression, keeping patient's state, perhaps or even chemoprophylaxis treatment, for example in the patient of ill risk is arranged, carries out the chemoprophylaxis treatment.
Therefore, formula (I) compound can use with other anti-proliferative compounds combination.Said anti-proliferative compounds includes but not limited to aromatase inhibitor; Antiestrogen; The topoisomerase I suppressor factor; The topoisomerase II suppressor factor; The microtubule active compound; Alkylated compound; Histone deacetylase inhibitor; The compound of inducing cell atomization; Cyclooxygenase inhibitors; The MMP suppressor factor; The mTOR suppressor factor; The antitumor activity metabolic antagonist; Platinic compound; Target in/reduce the compound of protein kinase or fat kinase activity; Anti-angiogenic compounds; Target is in, reduction or arrestin Phosphoric acid esterase or the active compound of lipophosphatidic acid enzyme (lipid phosphatase); Gonadorelin (gonadorelin) agonist; Antiandrogen; The methionine aminopeptidase suppressor factor; Diphosphonate; Biological respinse modifier; Antiproliferation antibodies; Heparanase (heparanase) suppressor factor; The suppressor factor of the carcinogenic isoform of Ras; Telomerase inhibitor; Proteasome inhibitor; Be used to treat the compound of hematology malignant diseases; Target in, reduce or suppress the active compound of Flt-3; The Hsp90 suppressor factor; Spindle body kinesin (kinesin spindle protein) suppressor factor; Mek inhibitor; LV; EDG binding substances (EDG binder); The leukemia compound; Ribonucleotide reductase inhibitor; The S adenosylmethionine decarboxylase suppressor factor; Blood vessel inhibition (angiostatic) steroid; Reflunomide; Other chemotherapy compound (such as hereinafter definition); Light-sensitive compound.
In addition; As alternative perhaps extraly; They can use with other tumor therapeuticing method combination; Said tumor therapeuticing method comprises operation, ionizing radiation, PDT, implant (implant that for example has reflunomide, hormone), and perhaps they can be used as radiosensitizer.
Term used herein " aromatase inhibitor " relates to and suppresses estrogen production, be the compound that substrate Androstenedione and testosterone transform to oestrone and Theelin,dihydro-respectively.This term includes but not limited to steroid; Especially SH 489, FCE-24304 and FORMESTAN; And particularly on-steroidal, especially aminoglutethimide, Rogletimide, Racemic pyridoglutethimide, Win-24540, testolactone, KETOKONAZOL, R 83842, Arensm, Anastrozole and letrozole.FCE-24304 can be for example with its commercial form, for example with the commercially available administered of trade mark AROMASIN.FORMESTAN can be for example with its commercial form, for example with the commercially available administered of trade mark LENTARON.Arensm can be for example with its commercial form, for example with the commercially available administered of trade mark AFEMA.Anastrozole can be for example with its commercial form, for example with the commercially available administered of trade mark ARIMIDEX.Letrozole can be for example with its commercial form, for example with trade mark FEMARA or the commercially available administered of FEMAR.Aminoglutethimide can be for example with its commercial form, for example with the commercially available administered of trade mark ORIMETEN.The combination that is included as the chemotherapeutic drug of aromatase inhibitor of the present invention is particularly useful for treating hormone receptor positive tumour, for example mammary tumor.
Term used herein " antiestrogen " relates to the compound of antagonism estrogen effect on the ERs level.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen can be for example with its commercial form, for example with the commercially available administered of trade mark NOLVADEX.RALOXIFENE HCL can be for example with its commercial form, for example with the commercially available administered of trade mark EVISTA.Fulvestrant can be like US 4,659, in 516 disclosed that kind prepare or its can be for example with its commercial form, for example with the commercially available administered of trade mark FASLODEX.The combination of the present invention that is included as the chemotherapeutic drug of antiestrogen is particularly useful for treating estrogen receptor positive tumors, for example mammary tumor.
Term used herein " antiandrogen " relates to any material that can suppress the male hormone biological action, includes but not limited to bicalutamide (CASODEX), and it can be for example like US 4,636, and disclosed that kind is prepared in 505.
Term used herein " goserelin agonist " includes but not limited to R 3827, goserelin and acetate goserelin.Goserelin is disclosed in US 4,100, in 274, can be for example with its commercial form, for example with the commercially available administered of trade mark ZOLADEX.R 3827 can be for example like US5, and disclosed that kind is prepared in 843,901.
Term used herein " topoisomerase I suppressor factor " includes but not limited to TPT, gefitinib, irinotecan, NSC 94600 and analogue thereof, 9-nitrocamptothecin and macromole NSC 94600 conjugates PNU-166148 (compd A 1 among the WO 99/17804).Irinotecan can be for example with its commercial form, for example with the commercially available administered of trade mark CAMPTOSAR.TPT can be for example with its commercial form, for example with the commercially available administered of trade mark HYCAMTIN.
Term used herein " topoisomerase II suppressor factor " includes but not limited to anthracycline compound; (comprise Liposomal formulation like Dx; CAELYX for example), daunorubicin, pidorubicin, idarubicin and Nemorubicin; Anthraquinone analog compound mitoxantrone and losoxantrone, and podophyllotoxin analogue VP and teniposide.VP can be for example with its commercial form, for example with the commercially available administered of trade mark ETOPOPHOS.Teniposide can be for example with its commercial form, for example with the commercially available administered of trade mark VM 26-BRISTOL.Dx can be for example with its commercial form, for example with trade mark ADRIBLASTIN or the commercially available administered of ADRIAMYCIN.Pidorubicin can be for example with its commercial form, for example with the commercially available administered of trade mark FARMORUBICIN.Idarubicin can be for example with its commercial form, for example with the commercially available administered of trade mark ZAVEDOS.Mitoxantrone can be for example with its commercial form, for example with the commercially available administered of trade mark NOVANTRON.
Term " microtubule active compound " relates to microtubule stable compound, microtubule stabilization removal compound and tubulin polymerization suppressor factor, includes but not limited to bearing taxanes, for example taxol and docetaxel; Vinca alkaloids, for example vinealeucoblastine(VLB), especially Vinblastine sulphate, vincristine(VCR), especially vincristine sulphate and vinorelbine; Wash rice suberite lactone; NSC-757.; With esperamicin and verivate thereof, for example epothilone B or D or derivatives thereof.Taxol can be for example with its commercial form, for example with the commercially available administered of TAXOL.Docetaxel can be for example with its commercial form, for example with the commercially available administered of trade mark TAXOTERE.Vinblastine sulphate can be for example with its commercial form, for example with the commercially available administered of trade mark VINBLASTIN R.P..Vincristine sulphate can be for example with its commercial form, for example with the commercially available administered of trade mark FARMISTIN.Wash rice suberite lactone can be for example like US 5,010, and disclosed that kind obtains in 099.Also comprise WO 98/10121, US6,194,181, disclosed esperamicin derivatives among WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and the WO 00/31247.Especially preferred is Epothilones A and/or B.
Term used herein " alkylated compound " includes but not limited to endoxan, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).Endoxan can be for example with its commercial form, for example with the commercially available administered of trade mark CYCLOSTIN.Ifosfamide can be for example with its commercial form, for example with the commercially available administered of trade mark HOLOXAN.
Term " histone deacetylase inhibitor " or " hdac inhibitor " relate to the inhibition of histone deacetylase and have the compound of antiproliferative activity.This comprises disclosed compound among the WO 02/22577, especially N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylic amide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylic amide and pharmacy acceptable salt thereof.It also especially comprises Vorinostat (SAHA).Target suppresses to be known as the activity of the enzyme of histone deacetylase in the compound of, reduction or inhibition of histone deacetylase (HDAC) inhibitor activity such as Sodium propanecarboxylate and Vorinostat (SAHA).Concrete hdac inhibitor comprises MS275, SAHA, FK228 (being FR901228 in the past), Trichostatin A and US 6; 552; Disclosed compound in 065; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylic amide or its pharmacy acceptable salt and N-hydroxyl-3-[4-[(2-hydroxyethyl) { 2-(1H-indol-3-yl) ethyl]-amino particularly] methyl] phenyl]-2E-2-acrylic amide or its pharmacy acceptable salt, especially lactic acid salt.
Term " antitumor activity metabolic antagonist " includes but not limited to 5 FU 5 fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compound such as 5-azacytidine and NSC 127716, methotrexate and edatrexate and antifol such as pemetrexed.Capecitabine can be for example with its commercial form, for example with the commercially available administered of trade mark XELODA.Gemcitabine can be for example with its commercial form, for example with the commercially available administered of trade mark GEMZAR.
Term used herein " platinic compound " includes but not limited to carboplatin, cis-platinum, cis-platinum and oxaliplatin.Carboplatin can be for example with its commercial form, for example with the commercially available administered of trade mark CARBOPLAT.Oxaliplatin can be for example with its commercial form, for example with the commercially available administered of trade mark ELOXATIN.
Term used herein " target in/reduce the compound of protein kinase or fat kinase activity "; Perhaps " target in/reduce the compound of phosphoprotein phosphatase or lipophosphatidic acid enzymic activity "; Perhaps " other anti-angiogenic compounds " includes but not limited to c-Met Tyrosylprotein kinase and/or Serine and/or threonine kinase enzyme inhibitors or lipid kinase inhibitors, for example,
A) target in, reduce or suppress the active compound of platelet derived growth factor receptor (PDGFR); As target in, reduce or suppress the active compound of PDGFR; Especially the compound that suppresses pdgf receptor; For example N-phenyl-2-pyrimidine-amine derivatives, for example imatinib, SU101, SU6668 and GFB-111;
B) target in, reduce or be suppressed to the active compound of bfgf receptor (FGFR);
C) target in, reduce or suppress the active compound of IGF-1 I (IGF-IR); As target in, reduce or suppress the active compound of IGF-IR; Especially the compound that suppresses the kinase activity of IGF-I acceptor; Like disclosed those compounds among the WO 02/092599, perhaps target is in the extracellular domain of IGF-I acceptor or the antibody of its growth factor;
D) target in, reduce or suppress the compound of Trk receptor tyrosine kinase family active, or liver is joined the suppressor factor of albumen (ephrin) kinases family;
E) target in, reduce or suppress the compound of Axl receptor tyrosine kinase family active;
F) target in, reduce or suppress the compound of Ret receptor tyrosine kinase activity;
G) target in, reduce or suppress the compound of Kit/SCFR receptor tyrosine kinase activity, for example imatinib;
H) target in, reduce or suppress C-kit receptor tyrosine kinase-(part of PDGFR family) active compound; As target in, reduce or suppress the compound of c-Kit receptor tyrosine kinase family active; Especially the compound that suppresses the c-Kit acceptor, for example imatinib;
I) target in, reduce or suppress c-Abl family member, their gene fusion product (for example BCR-Abl kinases) and the active compound of two mutants; As target in, reduce or suppress the active compound of c-Abl family member and their gene fusion product; N-phenyl-2-pyrimidine-amine derivatives for example, for example imatinib or Buddhist nun Lip river are for Buddhist nun (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; Or Dasatinib (BMS-354825);
J) target is in, reduction or arrestin kinase c (PKC) and the serine/threonine kinase member of Raf family and MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family member and/or the member's of cell cycle protein dependent kinase family (CDK) active compound; Especially US 5; 093; Disclosed those staurosporine derivatives, for example midostaurin in 330; Other examples for compounds comprises for example UCN-01, SPC 100270, BAY 43-9006, bryostatin 1, Perifosine; Thio ALP; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; Isoquinoline compound, as among the WO 00/09495 disclosed those; FTI; PD184352 or QAN697 (P13K suppressor factor) or AT7519 (CDK suppressor factor);
K) target is in, reduction or the active compound of arrestin tyrosine kinase inhibitor, comprises STI571 (GLEEVEC) or tyrphostin like target in, reduction or the active compound of arrestin tyrosine kinase inhibitor.Tyrphostin is lower molecular weight (Mr＜1500) compound preferably; Or its pharmacy acceptable salt; Especially be selected from the compound of tolylene propane dinitrile class or S-aryl phenylpropyl alcohol dintrile or Double bottom thing quinolines, more particularly be selected from following any compound: Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; TyrphostinAG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomorph; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{ [(2, the 5-dihydroxy phenyl) methyl] amino }-the phenylformic acid adamantane esters; NSC680410, adaphostin);
L) target in, reduce or suppress epidermal growth factor family (EGFR, ErbB2, ErbB3, the ErbB4 of receptor tyrosine kinase; For all-or the form of assorted-dipolymer) or their the active compound of two mutants; As target in, reduce or suppress the active compound of Epidermal Growth Factor Receptor Family especially suppress EGF receptor tyrosine kinase family member for example EGF acceptor, ErbB2, ErbB3 and ErbB4 or with EGF or EGF dependency part bonded compound, protein or antibody; Those disclosed compound, protein or monoclonal antibody: WO 97/02266 in following document prevailingly and particularly particularly; The compound of embodiment 39 for example; Perhaps EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, US 5; 747; 498, WO 98/10767, WO 97/30034, WO97/49688, WO 97/38983, and especially WO 96/30347 (compound that for example is called as CP358774), WO 96/33980 (for example compound ZD 1839) and WO 95/03283 (for example compound ZM105180); Trastuzumab (Herceptin for example TM), Cetuximab (Erbitux TM), disclosed 7H-pyrrolo-[2,3-d] pyrimidine derivatives among Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and the WO 03/013541; With
M) target in, reduce or suppress the compound of c-Met receptor active; As target in, reduce or suppress the active compound of c-Met; Especially the compound that suppresses the kinase activity of c-Met acceptor, perhaps target in the extracellular domain of c-Met or with HGF bonded antibody.
N) target in, reduce or suppress the compound of Ron receptor tyrosine kinase activity.
Other anti-angiogenic compounds comprise have other activity mechanism, for example with the compound of the irrelevant mechanism of protein kinase or fat kinase inhibitory activity, for example Thalidomide (THALOMID) and TNP-470.
" target is in the compound of, reduction or arrestin Phosphoric acid esterase or lipophosphatidic acid enzymic activity " includes but not limited to the suppressor factor of phosphatase 1, Phosphoric acid esterase 2A or CDC25, for example okadaic acid or derivatives thereof.
" compound of inducing cell atomization " for example include but not limited to vitamin A acid, α-, γ-or Delta-Tocopherol or α-, γ-or δ-tocotrienols.
Term used herein " cyclooxygenase inhibitors " includes but not limited to for example Cox-2 suppressor factor, 5-alkyl substituted 2-arylamino phenylacetic acid and verivate thereof, like celecoxib (CELEBREX), rofecoxib (VIOXX), L-791456, valdecoxib or 5-alkyl-2-arylamino phenylacetic acid 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid, Lu Mikao former times for example.
Term used herein " diphosphonate " includes but not limited to etidronic acid (etridonic acid), clodronic acid, tiludronic acid, pamidronic acid, clinic effect of alendronate, Ibandronic acid, risedronic acid and Zoledronic acid." etidronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark DIDRONEL." clodronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark BONEFOS." tiludronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark SKELID." pamidronic acid " can be for example with its commercial form, for example with trade mark AREDIA TMCommercially available administered." clinic effect of alendronate " can be for example with its commercial form, for example with the commercially available administered of trade mark FOSAMAX." Ibandronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark BONDRANAT." risedronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark ACTONEL." Zoledronic acid " can be for example with its commercial form, for example with the commercially available administered of trade mark ZOMETA.
Term " mTOR suppressor factor " relates to the compound that suppresses mammiferous rapamycin target (mTOR) and have antiproliferative activity, like sirolimus
Figure BDA0000151397020000331
SDZ-RAD (Certican TM), CCI-779 and ABT578.
Term used herein " heparanase inhibitors " be meant target in, reduce or suppress the compound of heparin sulfate degraded.This term includes but not limited to PI-88.
Term used herein " biological respinse modifier " is meant lymphokine or Interferon, rabbit, for example interferon-gamma.
Term used herein " suppressor factor of the carcinogenic isoform of Ras " (the carcinogenic isoform of said Ras is H-Ras, K-Ras or N-Ras for example) be meant target in, reduce or suppress the compound of the carcinogenic activity of Ras; For example " farnesyl transferase inhibitor ", for example L-744832, DK8G557 or R115777 (Zarnestra).
Term used herein " telomerase inhibitor " be meant target in, reduce or suppress the compound of telomerase activation.Target in, reduce or the compound that suppresses telomerase activation especially suppresses the compound of Telomerase acceptor, for example telomestatin.
Term used herein " methionine aminopeptidase suppressor factor " be meant target in, reduce or suppress the active compound of methionine aminopeptidase.Target in, to reduce or suppress the active compound of methionine aminopeptidase be bengamide or derivatives thereof for example.
Term used herein " proteasome inhibitor " is meant that target is in, reduction or the active compound of arrestin enzyme body.Target comprises for example Bortezomid (Velcade in, reduction or the active compound of arrestin enzyme body TM) and MLN 341.
Term used herein " NMPI " or (" MMP " suppressor factor) but include but not limited to collagen intend peptide and non-plan inhibitor peptides, tetracycline derivant for example hydroxamic acid intend analogue Marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or the AAJ996 of inhibitor peptides BB-94 and its oral biological utilisation.
Term used herein " is used to treat the compound of hematology malignant diseases " and includes but not limited to FMS-appearance tyrosine kinase inhibitor, for example target in, reduce or suppress the active compound of FMS-appearance tyrosine kinase receptor (Flt-3R); Interferon, rabbit, 1-b-D-arbinofuranose base cytosine(Cyt) (ara-c) and busulfan (bisulfan); With the ALK suppressor factor, for example target in, reduce or suppress the compound of Nucleophosmin-anaplastic lymphoma kinase.
Term " target in, reduce or suppress the active compound of FMS-appearance tyrosine kinase receptor (Flt-3R) " especially suppresses the member's of Flt-3R receptor kinase family compound, protein or antibody, for example PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.
Term used herein " HSP90 suppressor factor " include but not limited to target in, reduce or suppress the compound of the intrinsic atpase activity of HSP90; Via ubiquitin proteasome path degraded, target in, reduce or suppress the proteic compound of HSP90 client.Target in, reduce or the compound that suppresses the intrinsic atpase activity of HSP90 especially suppresses compound, protein or the antibody of the atpase activity of HSP90; 17-allyl amino for example; 17-de-methoxy NSC 122750 (17AAG, 17-DMAG)-geldanamycin derivant; The compound that other is relevant with NSC 122750; Radicicol and hdac inhibitor; IPI-504, CNF1010, CNF2024, from the CNF1010 of Conforma Therapeutics; TM
Figure BDA0000151397020000351
is from the AUY922 of Novartis.
Term used herein " antiproliferation antibodies " includes but not limited to trastuzumab (Herceptin TM), trastuzumab-DM1, Erbitux, shellfish cut down pearl monoclonal antibody (Avastin TM), Rituximab
Figure BDA0000151397020000352
PRO64553 (anti-CD 40) and 2C4 antibody.Multi-specificity antibody and antibody fragment that " antibody " means for example complete monoclonal antibody, polyclonal antibody, formed by at least 2 complete antibodies are as long as they show required BA.
Term " leukemia compound " comprises for example Ara-C-pyrimidine analogue, and it is 2 ' of Deoxyribose cytidine-Alpha-hydroxy ribose (cytosine arabinoside) verivate.Also comprise hypoxanthic purine analogue, Ismipur (6-MP) and NSC-328002.For the treatment of acute myeloid leukaemia (AML), formula (I) compound can use with the combination of standard white blood disease therapy, especially with the therapy combination use that is used to treat AML.Particularly, formula (I) compound medicine for example daunorubicin, Zorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and the PKC412 combined administration that can be used to treat AML with for example farnesyl transferase inhibitor and/or other.
" the somatostatin receptor antagonist " used herein be meant target in, reduce or suppress compound such as the Sostatin and the SOM230 of the somatostatin receptor.
" method of damage tumour cell " is meant such as methods such as ionizing radiations.Mentioned term " ionizing radiation " is meant the ionizing radiation that occurs with electromagnetic radiation (like X-ray and gamma-rays) or particle (like α and beta-particle) form in the context.Ionizing radiation provides in radiotherapy, but is not limited thereto, and is known in the art.Referring to Hellman, radiotherapeutic principle, cancer (Principles of Radiation Therapy, Cancer), Principles an d Practice of Oncology, people such as Devita edit, and the 4th edition, the 1st volume, 248-275 page or leaf (1993).
Term used herein " EDG wedding agent " is meant a para-immunity suppressor factor of regulating lymphocyte recycling, like FTY720.
Term " spindle body kinesin suppressor factor " is well known in the art, and comprises from the SB715992 of GlaxoSmithKline or SB743921, from pentamidine/CHLORPROMAZINE HCL of CombinatoRx;
Term " mek inhibitor " is well known in the art, and comprises ARRY142886, the AZD6244 from AstraZeneca, the PD181461 from Pfizer, LV from Array PioPharma.
Term " ribonucleotide reductase inhibitor " includes but not limited to pyrimidine or purine nucleoside analogs, includes but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-Tioguanine, 5 FU 5 fluorouracil, CldAdo, Ismipur (especially being used to resist ALL with the ara-C combination) and/or pentostatin.Ribonucleotide reductase inhibitor is hydroxyurea or 2-hydroxyl-1H-isoindole-1 especially, and the 3-derovatives is like people such as Nandy; Acta Oncologica; The 33rd volume, the 8th phase, the PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or the PL-8 that mention in the 953-961 page or leaf (1994).
Term used herein " S adenosylmethionine decarboxylase suppressor factor " includes but not limited to US5, disclosed compound in 461,076.
Also comprise particularly in WO 98/35958 (for example 1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazines or its pharmacy acceptable salt, for example SUMATRIPTAN SUCCINATE) or the monoclonal antibody of those disclosed compound, protein or VEGF/VEGFR in WO 00/09495, WO00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0769947; Described in the following document those: people such as Prewett, Cancer Res, the 59th volume, 5209-5218 page or leaf (1999); People such as Yuan, ProcNatlAcadSci USA, the 93rd volume, 14765-14770 page or leaf (1996); People such as Zhu, Cancer Res, the 58th volume, 3209-3214 page or leaf (1998); With people such as Mordenti, Toxicol Pathol, the 27th volume, the 1st phase, 14-21 page or leaf (1999); WO 00/37502 and WO94/10202; People such as O ' Reilly, Cell, the 79th volume, the ANGIOSTATIN described in the 315-328 page or leaf (1994); People such as O ' Reilly, Cell, the 88th volume, the ENDOSTATIN described in the 277-285 page or leaf (1997); The anthranilic acid acid amides; ZD4190; ZD6474; SU5416; SU6668; Shellfish is cut down the pearl monoclonal antibody; Or anti-VEGF antibodies or anti-VEGF receptor antibody, for example rhuMAb and RHUFab, VEGF is fit Macugon for example; FLT-4 suppressor factor, FLT-3 suppressor factor, VEGFR-2IgG1 antibody, Angiozyme (RPI 4610) and shellfish are cut down pearl monoclonal antibody (Avastin TM).
" PDT " used herein is meant that the chemical substance that adopts some to be called as light-sensitive compound is treated or the therapy of preventing cancer.The instance of PDT comprises the treatment of carrying out with for example compound such as VISUDYNE and porfimer sodium.
" blood vessel inhibition steroid " used herein is meant blocking-up or suppresses the compound of vasculogenesis, for example anecortave, triamcinolone, HYDROCORTISONE INJECTIONS, 11-α-epihydrocotisol, deoxidation KE, 17 α-hydroxyprogesterone, Kendall compound, Desoxycortone, testosterone, oestrone and DEXAMETHASONE BP98.
" reflunomide " used herein includes but not limited to for example compound such as fluocinolone acetonide, DEXAMETHASONE BP98; The said compound of implant form particularly.
" other chemotherapy compound " includes but not limited to plant alkaloid, hormonal compounds and antagonist; Biological respinse modifier, preferred lymphokine or Interferon, rabbit; Antisense oligonucleotide or oligonucleotide derivative; ShRNA or siRNA; Or mixed compounds (miscellaneous compounds) or have other mechanism of action or compound that the mechanism of action is unknown.
Formula (I) compound can also use with one or more other medicines combinations, and said other medicines are selected from anti-inflammatory drug; Antihistamine drug; Bronchiectasis medicine, NSAID; Chemokine receptor anagonists.
Compound of the present invention also can be used as the co-therapy compound and is used for using with said other medicines combination; Especially for treatment inflammatory diseases those inflammatory diseasess as mentioned above, for example as the synergistic agent of the therapeutic activity of said medicine or as the required dosage that reduces said medicine or the instrument of potential spinoff.Compound of the present invention can mix with said other medicines in the fixed drug compsn, perhaps can use respectively (that is, before other medicines are used, simultaneously or use afterwards).Therefore, the present invention includes the combination of formula (I) compound and one or more other medicines, said other medicines are selected from anti-inflammatory drug; Antihistamine drug; Bronchiectasis medicine, NSAID chemokine receptor anagonists; Said formula (I) compound and said medicine are in the identical or different pharmaceutical composition.
Suitable antiphlogiston comprises steroid; Particularly glucocorticosteroid such as budesonide, beclometasone (beclamethasone dipropionate), FP, ciclesonide or furoic acid momisone; The perhaps steroid described in WO 02/88167, WO 02/12266, WO 02/100879, WO 02/00679 (especially those among the embodiment 3,11,14,17,19,26,34,37,39,51,60,67,72,73,90,99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445, the WO 03/072592, those described in on-steroidal glucocorticoid receptor agonist such as WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, the WO 04/005229; Described in LTB4 antagonist such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247 and the US 5451700 those; LTD4 antagonist such as Singulair and Zafirlukast; PDE4 suppressor factor such as cilomilast (
Figure BDA0000151397020000381
GlaxoSmithKline); Roflumilast (Byk Gulden); V-11294A (Napp); BAY19-8004 (Bayer); SCH-351591 (Schering-Plough); Arofylline (Almirall Prodesfarma); PD189659/PD168787 (Parke-Davis); AWD-12-281 (Asta Medica); CDC-801 (Celgene); SelCID (TM) CC-10004 (Celgene); VM554/UM565 (Vernalis); T-440 (Tanabe); KW-4490 (KyowaHakko Kogyo) and WO 92/19594; WO 93/19749; WO 93/19750; WO93/19751; WO 98/18796; WO 99/16766; WO 01/13953; WO 03/104204; WO 03/104205; WO 03/39544; WO 04/000814; WO 04/000839; WO04/005258; WO 04/018450; WO 04/018451; WO 04/018457; WO 04/018465; WO 04/018431; WO 04/018449; WO 04/018450; WO 04/018451; WO04/018457; WO 04/018465; WO 04/019944; WO 04/019945; Described in WO 04/045607 and the WO 04/037805 those; A2a agonist such as EP 409595A2; EP 1052264; EP 1241176; WO 94/17090; WO 96/02543; WO 96/02553; WO 98/28319; WO 99/24449; WO 99/24450; WO 99/24451; WO 99/38877; WO 99/41267; WO 99/67263; WO 99/67264; WO 99/67265; WO 99/67266; WO 00/23457; WO 00/77018; WO 00/78774; WO 01/23399; WO 01/27130; WO 01/27131; WO 01/60835; WO 01/94368; WO 02/00676; WO 02/22630; WO 02/96462; WO 03/086408; WO 04/039762; WO 04/039766; Described in WO 04/045618 and the WO04/046083 those; Described in A2b antagonist such as the WO 02/42298 those; With beta-2-adrenoceptor agonist such as salbutamol (salbutamol), Orciprenaline, terbutaline, Salmeterol, Partusisten, procaterol and especially formoterol with and pharmacy acceptable salt; With the formula I compound (free form or salt form or solvate form thereof) among the WO 0075114; With the document by reference mode integrate with among this paper; Compound, the especially formula of preferred embodiment
The compound and the pharmacy acceptable salt thereof of
Figure BDA0000151397020000391
; And the formula I compound among the WO04/16601 (free form or salt form or solvate form thereof), also have the compound among the WO04/033412.
Suitable bronchodilator comprises anticholinergic compound or antimuscarinic compounds; Particularly ipratropium bromide, oxitropium bromide, tiotropium salt and CHF 4226 (Chiesi); And GLYCOPYRRONIUM (glycopyrrolate), those described in WO 01/04118, WO 02/51841, WO 02/53564, WO03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US 5171744, US 3714357, WO 03/33495 and the WO 04/018422 in addition.
Suitable Chemokine Receptors comprises for example CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonist; [[4-[[[6 like the antagonist of antagonist SC-351125, SCH-55700 and the SCH-D of Schering-Plough, Takeda such as chlorination N-; 7-dihydro-2-(4-aminomethyl phenyl)-5H-benzo-suberene-8-yl] carbonyl] amino] phenyl]-methyl] tetrahydrochysene-N; CCR-5 antagonist described in N-dimethyl--2H-pyrans-4-ammonium (TAK-770) and US 6166037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and the WO 04/026873.
Suitable antihistamine drug comprises cetrizine hcl; PARACETAMOL BP98; Clemastine fumarate; Promethazine; LT (loratidine); Desloratadine; Diphenhydramine and fexofenadine hydrochloride; Acrivastine (activastine); Astemizole; Nitrogen
Figure BDA0000151397020000392
Si Ting; Ebastine; Epinastine; Mizolastine and Te Fennading (tefenadine) and WO 03/099807; Described in WO 04/026841 and the JP2004107299 those.
Especially one or more are antiproliferative for the therapeutical agent that is used for possible combination, suppress cell or Cytotoxic compounds, and for example one or more are selected from the material of following group, and this group includes but not limited to: the polyamines biosynthesis inhibitor; Kinases inhibitor; Especially serine/threonine protein kitase suppressor factor; Like inhibitors of protein kinase C or tyrosine protein kinase inhibitor, like EGF receptor tyrosine kinase inhibitors for example antibody or pdgf receptor tyrosine kinase inhibitor for example STI571
Figure BDA0000151397020000403
PI3K (like BEZ235) and the thunderous handkerchief mycin of mToR suppressor factor, the RAD001 of PTK787 or
Figure BDA0000151397020000402
anti-part VEGF of vegf receptor tyrosine kinase suppressor factor for example from Novartis; Cytokine-a kind of negative growth regulator is like TGF-β or IFN-β; Aromatase inhibitor, for example letrozole or Anastrozole; The interactional suppressor factor of SH2 structural domain and phosphorylated protein; Antiestrogen; The topoisomerase I suppressor factor is like irinotecan; The topoisomerase II suppressor factor; Microtubule active agent, for example taxol or esperamicin; Alkylating agent; The anti proliferative metabolic antagonist is like gemcitabine or capecitabine; Platinic compound is like carboplatin or cis-platinum; Diphosphonate; For example
Figure BDA0000151397020000405
or and monoclonal antibody; The monoclonal antibody of anti-HER2 for example is like trastuzumab.
The structure of the promoting agent that is identified through Code Number, popular name or trade(brand)name can for example obtain the Patents International (for example IMSWorld Publications) from the current edition of standard directories " the Merck index " or from DB.With its content corresponding by reference mode integrate with among this paper.
The compound mentioned above that can use with formula (I) compound combination can prepare as in this area, described in the document quoted of for example preceding text and use.
In combined therapy of the present invention, compound of the present invention can be produced and/or preparation by identical or different manufacturer with other therapeutical agent.In addition; Compound of the present invention and other therapeutical agent can (i) before combined prod is offered the doctor (for example; Under the situation of the medicine box that comprises compound of the present invention and other therapeutical agent), (ii) using before in the short period of time by doctor self (perhaps instructing down), (iii) by patient self the doctor, for example in the process of sequential application compound of the present invention and other therapeutical agent, be used for combined therapy together by patient self.Correspondingly, the invention provides formula (I) compound and be used to treat by the disease of cMet mediation or the purposes of illness, wherein medicament is produced and is used for using with another kind of therapeutical agent.The present invention also provides another kind of therapeutical agent to be used to treat by the disease of cMet mediation or the purposes of illness, and wherein medicament is used with formula (I) compound.
Therefore, the present invention relates to combination in an other embodiment, pharmaceutical composition particularly, and it comprises the free form of treating significant quantity or formula (I) compound and second kind of therapeutic activity agent of pharmacy acceptable salt form, is used for simultaneously or sequential application.This other therapeutical agent is preferably selected from anticarcinogen, antiphlogiston.
The invention still further relates to treatment has disease or obstacle, especially proliferative disorder or disease, the particularly method for cancer of response, said method to comprise to what its individuality, especially people of needs used significant quantity to the C-Met Tyrosylprotein kinase to comprise (a) formula (I) compound and (b) drug regimen of one or more forms of pharmacologically active agents.
The invention still further relates to and comprise (a) formula (I) compound and be used to treat with (b) drug regimen of one or more forms of pharmacologically active agents the C-Met Tyrosylprotein kinase is had the disease of response or the purposes of obstacle, especially proliferative disorder or disease, particularly cancer.
The invention still further relates to the purposes of drug regimen in the preparation medicament that comprises (a) formula (I) compound and (b) one or more forms of pharmacologically active agents; Said medicament is used to treat disease or the obstacle that the C-Met Tyrosylprotein kinase is had response; Especially proliferative disorder or disease, particularly cancer.
The invention still further relates to pharmaceutical composition, it comprises (a) formula (I) compound and (b) forms of pharmacologically active agents; (c) pharmaceutically acceptable carrier; Wherein at least a forms of pharmacologically active agents is an anticancer therapeutic agent.
The invention still further relates to commercial cover cartridge bag (package) or product, it comprises: (a) formula (I) compound; The pharmaceutical prepn of the forms of pharmacologically active agents that (b) is used for simultaneously, walks abreast, distinguishes or uses in succession; Wherein at least a forms of pharmacologically active agents is an anticancer therapeutic agent.
Two kinds or more kinds of also be possible with the combination of using simultaneously in succession, respectively; The preferred component drug of combination that makes shows the combination therapy effect; This combination therapy effect surpasses viewed effect when the component drug of said combination is independently used can not observe the interactional timed interval of its therapeutic efficiency, especially preferably synergy.
The present invention also provides formula (I) compound to be used to treat by the disease of cMet mediation or the purposes of illness, and wherein treat with another kind of therapeutical agent (for example in 24 hours) before the patient.The present invention also provides another kind of therapeutical agent to be used to treat by the disease of cMet mediation or the purposes of illness, and wherein formula (I) compounds for treating has been used in (for example in 24 hours) before the patient.
Term used herein " postpone ... progress " mean to be in disease to be treated occur first or the stage in advance (pre-stage) and the early stage patient of recurrence use combination; Wherein the patient for example the form in advance (pre-form) of corresponding disease diagnose or this patient is in the situation that perhaps accident causes in the situation during therapeutic treatment for example, corresponding disease possibly take place in this case.
Term " combination therapy is active " or " combination therapy effect " mean compound and can distinguish at a certain time interval (with long-term staggered mode; Especially in proper order specific mode) give, the said timed interval makes them preferably still show (preferably working in coordination with) interaction (combination therapy effect) at Mammals, the especially philtrum of being treated.The combination therapy effect especially can confirm through following the trail of blood level, and it shows at least, and interim two kinds of compounds all are present in the people's who is treated the blood between some time.
Term " pharmacy is effective " preferably relates to treats or in the effective amount of the progress of antagonism disease disclosed herein or illness in prevention also on the wideer implication.
Term used herein " commercial cover cartridge bag " or " product " have especially defined " cover medicine box "; Implication is the defined component of preceding text (a) and (b) administration or use component (a) with different amounts and different fixed (b) makes up and carries out administration independently; That is, simultaneously or in the administration of different time point.In addition; These terms comprise commercial cover cartridge bag; It comprises (especially having made up) as the component (a) of activeconstituents and (b); And in progress that postpones proliferative disease or treatment proliferative disease its use simultaneously, use in succession (long-term staggered, use with specific time sequence, preferentially) or (preferably less) specification sheets of using respectively.Then can with each integral part of cover medicine box for example simultaneously or staggered in time (that is, different time point and with equate or different time intervals) use any integral part that overlaps medicine box.Most preferably, the timed interval is selected so as to make up use each integral part to the effect of the disease of being treated than only use COMBINATION OF THE INVENTION (a) with (b) in any effect that is obtained bigger (as can be according to standard method mensuration).The ratio of the total amount of the total amount of COMBINATION OF THE INVENTION (a) to be used and COMBINATION OF THE INVENTION (b) can change in the combination preparation; For example so that adapt to the needs of patient subgroups to be treated or the needs of single patient, said different needs possibly be because patient's disease specific, age, sex, body weight etc. cause.Preferably; There is at least a beneficial effect; The for example mutual enhancing of COMBINATION OF THE INVENTION (a) and effect (b), particularly greater than the effect of addition, its therefore can with every kind of medicinal composition respectively than only with single medicine but not the lower dosage of dosage that can tolerate during combined therapy reach; Thereby produce other advantageous effect; For example less spinoff or (a) with under (b) one or both of the non-effective dose produce the combined therapy effect in COMBINATION OF THE INVENTION (component), and most preferably, COMBINATION OF THE INVENTION (a) and strong synergy (b).
Using component (a) and combined prod (b) and using under two kinds of situation of commercial package; All be possible with the arbitrary combination of using respectively in succession simultaneously; This means component (a) and (b) can use simultaneously at the same time; (for example be longer than 3-4 week) chronically and only use a kind of component with being administered once every day with the lower main body toxicity of accepting at a slower time point then, use combination (in drug regimen therapeutic process subsequently, reaching best effect) of another kind of component or two kinds of components etc. subsequently at a further slower time point.
In another embodiment of the invention, the method for preparing formula (I) compound and its midbody is provided.Formula (I) is not though compound can be through being used for new compound of the present invention (therefore they form novel method in this case), still known method preparation own so far.Schema provides the general synthesis strategy general introduction of acquisition formula (I) compound.Only if this paper has explanation or clear from context to show opposite content in addition, otherwise described all methods all can be carried out according to the order of any appropriate.The use of any one instance that this paper provides or illustrative language (for example " as ") only is intended to explain better the present invention, does not constitute the restriction to the scope of the invention that requires to protect.
Therefore, in yet another aspect, the present invention relates to comprise preparing method's (method for preparing formula (I) compound) of formula (I) compound of at least one reactions step disclosed herein, and its midbody.
Schema 1
Figure BDA0000151397020000431
Z 1Be selected from Cl, Br and I
Schema 2 provides the details that obtains the synthesis strategy of preferred formula (IA, IB, IC) compound through (IIA, IIB and IIC).
Schema 2
Figure BDA0000151397020000441
Z 1And Z 2Be independently selected from Cl, Br and I
Schema 3 provides the details that obtains the synthesis strategy of preferred formula (ID) compound through (IID).
Schema 3
Figure BDA0000151397020000442
Z 1Be selected from Cl, Br and I
Schema 4 provides the details that obtains the synthesis strategy of preferred formula (IE) compound through (IIE).
Schema 4
Figure BDA0000151397020000451
Z 1Be selected from Cl, Br and I
Schema 5 provides the details that obtains the synthesis strategy of preferred formula (IF) compound through (IIF).
Schema 5
Figure BDA0000151397020000452
Z 1And Z 2Be independently selected from Cl, Br and I
Use well known to a person skilled in the art that method carries out oxidation, obtains SO/SO 2Linking group
Schema 6 provides the details that obtains the synthesis strategy of preferred formula (IG) compound through (IIG).
Schema 6
Figure BDA0000151397020000453
Schema 7 provides the details that obtains the synthesis strategy of preferred formula (IH) compound through (IIH).
Schema 8 provides the details that obtains the synthesis strategy of preferred formula (IK) compound through (IIK).
Schema 8
Figure BDA0000151397020000462
The for example clear the present invention of the following example, but do not limit the scope of the invention.In the embodiment that is provided, temperature is all with a degree centigrade measurement.Except as otherwise noted, otherwise react on room temperature and carry out.In addition, if not opposite explanation, it is following to analyze the HPLC condition:
Method A:
Flow velocity is 0.5mL/min first alcohol and water (having 0.5% acetate)
0-4.0min:10% to 90% methyl alcohol
4.0-6.0min:90% methyl alcohol
Post: from GP C183 μ m 4.6 * 30mm of Sepax
Column temperature: 30 ℃
Method B:
Flow velocity is 1.2mL/min first alcohol and water (having 0.5% acetate)
0-2.0min:10% to 90% methyl alcohol
2.0-3.0min:90% methyl alcohol
Post: from GP C183 μ m 4.6 * 30mm of Sepax
Column temperature: 30 ℃
Method C:
Flow velocity is 0.5mL/min first alcohol and water (having 0.5% acetate)
0-3.0min:60% to 90% methyl alcohol
3.0-5.0min:90% methyl alcohol
Post: from GP C183 μ m 4.6 * 30mm of Sepax
Column temperature: 30 ℃
Method D:
Flow velocity is 0.5mL/min first alcohol and water (having 0.5% acetate)
0-3.0min:10% to 50% methyl alcohol
3.0-4.0min:50% methyl alcohol
Post: from GP C183 μ m 4.6 * 30mm of Sepax
Column temperature: 30 ℃
Method E:
Flow velocity is 0.5mL/min first alcohol and water (having 0.5% acetate)
0-4.0min:10% to 90% methyl alcohol
4.0-8.0min:90% methyl alcohol
Post: from GP C183 μ m 4.6 * 30mm of Sepax
Column temperature: 30 ℃
Method F:
Flow velocity is 1mL/min hexane/ethanol/diethylamine 60/40/0.1, v/v/v
Post: CHIRALPAK AD-H, 4.6 * 150mm
Column temperature: 35 ℃
Method G:
Flow velocity is 1mL/min hexane/isopropyl alcohol/diethylamine 70/30/0.1, v/v/v
Post: CHIRALPAK AD-H, 4.6 * 150mm
Column temperature: 35 ℃
In the following example, used abbreviation given below:
AcOH acetate
Atm. normal atmosphere
BINAP 2,2 '-two-diphenylphosphino-[1,1 '] dinaphthalene
The Bn benzyl
The Boc tert-butoxycarbonyl
The DCM methylene dichloride
DME 1, the 2-glycol dimethyl ether
Et 2The O ether
EtOAc or EA ETHYLE ACETATE
EtOH ethanol
The DCC NSC 57182
DME dimethyl-terepthaloyl moietie (dimethyl ethylene glycol)
DMF N, dinethylformamide
The DMSO DMSO 99.8MIN.
Eq. equivalent
H hour
HATU phosphofluoric acid 2-(1H-7-azepine benzo triazol-1-yl)-1,1,3, the 3-tetramethyl-urea
Figure BDA0000151397020000481
The HPLC HPLC
The HV high vacuum
IBX 2-iodoxybenzene formic acid
Isolute International Solvent Technology Ltd.,
Figure BDA0000151397020000482
of U.K
HM-N
The LAH lithium aluminum hydride
LCMS and mass spectroscopy link coupled liquid phase chromatography
The LDA lithium diisopropylamine
The mL milliliter
Min minute
MPLC medium pressure liquid chromatography method
The MS-ES electron spray mass spectrometry
The MW microwave
The NBS N-bromo-succinimide
N-BuLi just-butyllithium
The NMP N-Methyl pyrrolidone
PdCl 2(dPPf) 1, two (diphenylphosphino) ferrocene palladium chlorides (II) of 1-
Pd 2(dba) 3Three (dibenzalacetones), two palladiums (0)
PdCl 2(Ph 3) 2Two (triphenyl phosphine) palladiums (II) of dichloro
PL PolymerLabs (cylinder (cartridge) supplier)
The RM reaction mixture
R fRf value among the TLC (ratio of front)
The SPE SPE
The rt room temperature
The TBAF tetrabutylammonium
The TBME MTBE
The TFA trifluoroacetic acid
The THF THF
The TLC tlc
t RRT
The UV ultraviolet
Synthesizing of midbody:
Intermediate A
3-bromo-6-chlorine imidazo [1,2-b] pyridazine
Figure BDA0000151397020000491
To 6-chlorine imidazo [1,2-b] pyridazine (5g 32.6mmol) adds 1-bromine tetramethyleneimine-2 in the solution in acetonitrile (300ml), the 5-diketone (6.37g, 35.8mmol) and trifluoroacetic acid (0.75mL).With the solution of gained in stirred overnight at room temperature.Under reduced pressure remove and desolvate, resistates is dissolved among the EtOAc, use NaHCO 3Solution, water and brine wash are used Na 2SO 4Dry also vacuum concentration obtains the 7.2g title compound, and yield 92% is faint yellow solid. 1H-NMR(400MHz，CDCl 3)δppm7.91(d，1H)，7.79(s，1H)，7.12(d，1H)。LCMS (method A): [MH] +=232/234, t R=4.48min.
Intermediate B
1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-ethyl ketone
Figure BDA0000151397020000501
N '-(6-chloro-pyridazine-3-yl)-N, N-dimethyl--carbonamidine (i)
With 3-amino-6-chlorine pyridazine (1.3g, 10mmol) and dimethylformamide dimethyl acetal (1.35ml, mixture 10.2mmol) obtains brown solid in refluxing down heating 2h and under vacuum, concentrating.Behind the EtOAc recrystallization, obtain 1.5g N '-(6-chloro-pyridazine-3-yl)-N, N-dimethyl--carbonamidine, yield 81%.
1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-ethyl ketone (intermediate B)
To N '-(6-chloro-pyridazine-3-yl)-N, N-dimethyl--carbonamidine (1.3g, 7mmol) add in the solution in DMF (60mL) NaI (1g, 6.7mmol) and monochloroacetone (1mL, 12.6mmol).Mixture in 80 ℃ of heated overnight, is under reduced pressure concentrated then.With column chromatography purifying resistates, obtain 1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-ethyl ketone (0.7g), yield 51%. 1H-NMR(400MHz，CDCl 3)δppm?8.42(s，1H)，8.05(d，1H)，7.31(d，1H)，2.77(s，3H)。
Midbody C
6-chloro-imidazo [1,2-b] pyridazine-3-formaldehyde
Figure BDA0000151397020000502
(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-methyl alcohol (i)
To 6-chlorine imidazo [1,2-b] pyridazine (1.5g, 9.8mmol) add in the solution in AcOH (50mL) NaOAc (1.4g, 17.1mmol) and paraformaldehyde (1.5g).Mixture in the heated overnight down that refluxes, is under reduced pressure concentrated then.Resistates is alkalized to pH=12.Filtering mixt washs solid with EtOH then, obtains (6-chloro-imidazo [1,2-b] pyridazine-3-yl)-methyl alcohol (1.3g), yield 72%.
6-chloro-imidazo [1,2-b] pyridazine-3-formaldehyde (midbody C)
(1.3g 7.1mmol) adds active MnO in the solution in DCM (50mL) to (6-chloro-imidazo [1,2-b] pyridazine-3-yl)-methyl alcohol 2(3g, 34.5mmol).Mixture in stirred overnight at room temperature, is filtered then.Concentrated filtrate under vacuum washs resistates with EtOAc, obtain 6-chloro-imidazo [1,2-b] pyridazine-3-formaldehyde (0.7g), yield 54%. 1H-NMR(400MHz，CDCl 3)δ10.36(s，1H)，8.42(s，1H)，8.08(d，1H)，7.38(d，1H)。
Midbody D
Quinoline-6-base methylamine
Quinoline-6-base methyl alcohol (i)
(14g 74.8mmol) divides many parts and adds LiAlH in the solution in THF (80mL) to quinoline-6-methyl-formiate 4(2.84g, 74.8mmol).Drip then water (2.84mL) and NaOH (10%, 4.26mL), with the excessive reductive agent of cancellation.After stirring other 20min, add ether, filter the mixture of gained through celite.Concentrated filtrate obtains resistates, and (hexane: EtOAc) purifying obtains quinoline-6-base methyl alcohol (7.6g), yield 64% with silica gel with it.
2-(quinoline-6-ylmethyl) isoindoline-1, the 3-diketone (ii)
Go through 30min; To in 0 ℃ isoindoline-1, and the 3-diketone (6.47g, 44.0mmol) and triphenyl phosphine (11.53g; 44.0mmol) drip quinoline-6-base methyl alcohol (7g in the solution in THF (70mL); 44.0mmol) solution in THF (30mL) with (E)-diazene-1,2-dioctyl phthalate diisopropyl ester (8.89g, 44.0mmol).Then mixture heating up to 30 ℃ is reached 20h.With reaction cooled to room temperature and vacuum concentration.(the gradient hexane: the EtOAc) resistates of purifying gained obtains 2-(quinoline-6-ylmethyl) isoindoline-1,3-diketone (12.04g), yield 95% with Analogix silica gel.LCMS (method A): [MH] +=2.99, t R=4.89min.
Quinoline-6-base methylamine (midbody D)
To 2-(quinoline-6-ylmethyl) isoindoline-1, the 3-diketone (20g, 69.4mmol) add in the solution in MeOH (100mL) Hydrazine Hydrate 80 (3.47g, 69.4mmol).Solution is heated to backflow reaches 3h, be cooled to room temperature then, filter through celite.Vacuum concentrated filtrate adds EtOAc with the dilution resistates, filters, and vacuum concentration obtains 6-bromo-N2-(quinoline-6-ylmethyl) pyrazine-2,3-diamines (5g), yield 41%.LCMS (method B): [MH] +=159, t R=0.93min.
Intermediate E and F
7-fluoro-quinoline-6-formaldehyde and 7-(7-fluoro-quinoline-6-yl)-methylamine
Figure BDA0000151397020000521
6-bromo-7-fluorine quinoline (i)
To 4-bromo-3-fluoro-phenyl amine (100g, 526mmol) add in the suspension in the vitriol oil (290mL) glycerine (220g, 2.39mol, 4.5eq.), add then ferrous sulfate (30g, 0.2eq.).Reaction mixture in 130 ℃ of heating 14h, is cooled to room temperature and pours in the frozen water.Solution is neutralized to pH 8 and extracts (2L * 3) with DCM with saturated ammonium hydroxide aqueous solution.The organic layer that merges with brine wash (1L * 3), with dried over sodium sulfate and under reduced pressure concentrated, is obtained crude product; Be brown solid, (oil: purifying ETHYLE ACETATE=10: 1) obtains 6-bromo-7-fluorine quinoline with column chromatography with it; Be white solid (45g, 39%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.86(s，1H)，8.56(m，1H)，8.45(m，1H)，7.90(d，1H)，7.71(m，1H)。
7-fluoro-quinoline-6-formaldehyde (intermediate E)
To Pd (PPh 3) 4(1.27g, 1.1mmol) and sodium formiate (13.8g, 132mmol 6e.q.) add 6-bromo-7-fluorine quinoline (5g, 22mmol) solution in DMSO (30mL) in the suspension in acetonitrile (30mL).With reaction mixture under CO atmosphere (1MPa) in 120 ℃ of heating 4h, be cooled to room temperature and under reduced pressure concentrate.Resistates is distributed between water (100mL) and ETHYLE ACETATE (150mL).Separate organic layer,, use Na with salt solution (100mL) washing 2SO 4Dry and under reduced pressure concentrated.Resistates is used the column chromatography purifying, use oil: ETHYLE ACETATE=10: 1～3: 1 wash-outs, obtain title compound, be white solid (400mg, 10.4%). 1H-NMR(400MHz，DMSO-d 6)δppm8.95(s，1H)，8.46(m，1H)，8.20(m，1H)，7.75(d，1H)，7.53(m，1H)。7-(7-fluoro-quinoline-6-yl)-methylamine (midbody F)
With 7-fluoro-quinoline-6-formaldehyde (500mg, 2.85mmol) be dissolved in ammonia solution (solution of 2M in MeOH, 50mL) in.After 3 hours, divide many parts to add NaBH in stirring at room 4(108.0mg, 2.85mmol).With the reaction mixture stirred overnight, water cancellation in ice bath.Under reduced pressure remove methyl alcohol, dilute with water resistates then transfers to the pH value of solution about 8 with 1N HCl solution, then with DCM extraction three times.The organic layer that merges is used water washing, use Na 2SO 4Drying is filtered and vacuum concentration.With chromatography (DCM: MeOH=50: 1) purifying crude product, obtain title compound, be yellow solid (250.0mg, 49%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.86(dd，1H)，8.36(d，1H)，8.07(d，1H)，7.68(d，1H)，7.49(dd，1H)，3.93(s，2H)，1.98(s，2H)。
Midbody G
1-(7-fluorine quinoline-6-yl) ethamine
Figure BDA0000151397020000531
1-(7-fluorine quinoline-6-yl) ethanol (i)
To in 7-fluorine quinoline-6-formaldehyde of 0 ℃ (4.0g, 22.84mmol) drip in the solution in THF (30ml) methylmagnesium-bromide (solution of 2.85M in THF, 8mL, 22.84mmol).With solution stirring 2h, add NH 4Cl reacts with cancellation.With the mixture of EtOAc extraction gained, organic layer is used saturated NaHCO 3And NH 4Na is used in the Cl washing 2SO 4Drying is filtered and is concentrated, and obtains crude product, and (use hexane: EtOAc) purifying obtains 1-(7-fluorine quinoline-6-yl) ethanol (i) with Analogix silica gel with it.LCMS (method B): [MH] +=192, t R=1.84min.
2-(1-(7-fluorine quinoline-6-yl) ethyl) isoindoline-1, the 3-diketone (ii)
Be similar to the title compound that synthesized by 1-(7-fluorine quinoline-6-yl) ethanol preparation of midbody D, be white solid.LCMS (method B): [MNa] +=353, t R=1.95min.
1-(7-fluorine quinoline-6-yl) ethamine (midbody G)
Be similar to the synthetic by 2-(1-(7-fluorine quinoline-6-yl) ethyl) isoindoline-1 of midbody D, the 3-diketone has prepared title compound.
Midbody H
5,7-two fluoro-quinoline-6-formaldehyde
Figure BDA0000151397020000541
With 5, (10.0g 77.5mmol) is dissolved among the DMF (100mL) 7-two fluoro-phenyl amine.Then in room temperature drip NBS (13.9g, 78.0mmol).After stirred overnight at room temperature, reaction mixture is used Et 2The O dilution is also used brine wash.With the dry (Na of isolating organic phase 2SO 4) and concentrate, obtain oily matter, it is used the column chromatography purifying, obtain 4-bromo-3,5-two fluoro-phenyl amine (i) (12.9g, 80.2%)
With 4-bromo-3, and 5-two fluoro-phenyl amine (i) (6.0g, 28.8mmole), the mixture mild heat of 1.82g ferrous sulfate, 8.6mL glycerine, 1.79mL oil of mirbane and the 5.0mL vitriol oil.For the first time behind the vigorous reaction, with mixture boiling 5 hours.Remove oil of mirbane through vacuum distilling.Use the glacial acetic acid acidified aqueous solution, isolate the dark-brown throw out, it through flash chromatography method (silica gel, oil/ETHYLE ACETATE=12/1) purifying, is obtained 6-bromo-5, the 7-difluoro-quinoline (ii) is white solid (3.5g, 49.8%).
To in-78 ℃ 6-bromo-5, the 7-difluoro-quinoline (ii) (250g, 1.02mol) drip in the solution in anhydrous THF (2200mL) solution of n-BuLi in hexane (2.5M, 408ml, 1.02mol).The mixture of gained is stirred other 30min in-78 ℃.Then, (79mL, the 1.02mol) solution in anhydrous THF (200mL) keep temperature to be lower than-70 ℃ simultaneously, and mixture is stirred 30min under uniform temp to add DMF.Reaction mixture slowly is warmed to room temperature, uses NH 4Cl saturated aqueous solution (1000mL) and water (800mL) dilution.Mixture with ethyl acetate extraction twice, with the organic layer water and the brine wash that merge, is also concentrated with anhydrous sodium sulfate drying; Obtain brown oil, it is passed through the silica gel column chromatography purifying, with oil and ETHYLE ACETATE (10: 1) wash-out; Obtain 5; 7-two fluoro-quinoline-6-formaldehyde (midbody H) is yellow solid (100g, 50%). 1H?NMR(DMSO，300MH)δ(ppm)：10.38(s，1H)，9.10～9.12(m，1H)，8.62～8.66(m，1H)，7.68～7.78(m，2H)
Intermediate compound I
1-methyl isophthalic acid H-indazole-5-formaldehyde
5-bromo-1H-indazole (i)
With 5-bromo-2-fluorobenzaldehyde (10.15g, 50mmol), MeONH 2-HCl (4.07g, 50mmol) and K 2CO 3(7.59g, 55.0mmol) suspension in 100mL DME stirred 5 hours in 40 ℃.Filtering mixt.Vacuum concentration contains the filtrating of oxime midbody, obtains about 50mL resistates.In this spissated oxime resistates, add N 2H 4-H 2(50mL's O 1.03mol), spends the night the mixture backflow.After reaction is accomplished, the vacuum concentration reaction mixture.With residue diluted with water, use the EtOAc extracted twice.Merge organic layer, use Na 2SO 4Dry and concentrate, obtain resistates, with its with the flash chromatography method (hexane: EtOAc=10: 1) purifying, obtain title compound, be white solid (6.02g, 61.2%). 1H-NMR(400MHz，DMSO-d 6)δppm?13.24(bs，1H)，9.85(s，1H)，8.05(s，1H)，7.99(s，1H)，7.52(d，1H)，7.44(dd，1H)。LCMS (method A): [MH] +=197/199, t R=4.94min.
(ii) methyl-the 2H-indazole (iii) with 5-bromo-2-for 5-bromo-1-methyl isophthalic acid H-indazole
To in 0 ℃ 5-bromo-1H-indazole (0.19g, 0.94mmol) add in the solution in 3mL THF NaH (0.04g, 1.03mmol).Reaction soln was stirred 1 hour in this temperature, then in 0 ℃ add methyl-iodide (0.09mL, 1.41mmol).Make sluggish be warmed to room temperature, stirred water cancellation and vacuum concentration 2 hours.With residue diluted with water, use the DCM extracted twice.Merge organic layer, use Na 2SO 4Dry and concentrated.With the flash chromatography method (hexane: EtOAc=10: 1) purifying crude product, obtain title compound ii (88.7mg, 42.5%) and iii (60.9mg, 29%), be two kinds of white solids.ii： 1H-NMR(400MHz，DMSO-d 6)δppm?8.02(d，1H)，7.99(d，1H)，7.64(d，1H)，7.50(dd，1H)，4.04(s，3H)。LCMS (method A): [MH] +=211/213, t R=5.19min.iii： 1H-NMR(400MHz，DMSO-d 6)δppm?8.33(s，1H)，7.95(d，1H)，7.57(d，1H)，7.30(dd，1H)，4.16(s，3H)。LCMS (method A): [MH] +=211/213, t R=4.95min.
1-methyl isophthalic acid H-indazole-5-formaldehyde (intermediate compound I)
With n-BuLi (7.33mL, 11.73mmol) and ethyl-magnesium-bromide (5.76mL, 5.76mmol) suspension in 30mL toluene stirs 30min in-30 ℃, be added in then 5-bromo-1-methyl isophthalic acid H-indazole among the 5mL THF (2.25g, 10.66mmol).In-10 ℃ stir 1 hour after, in-10 ℃ add dry DMF (4.95mL, 64.0mmol).Make reaction be warmed to room temperature and stirred 2 hours.With 1N HCl cancellation reaction and vacuum concentration.With residue diluted with water, use the DCM extracted twice.Merge organic layer, use Na 2SO 4Dry and concentrated.With the flash chromatography method (hexane: EtOAc=10: 1) purifying crude product, obtain title compound, be white solid (1.37g, 76%). 1H-NMR(400MHz，DMSO-d 6)δppm?10.02(s，1H)，8.41(d，1H)，8.31(d，1H)，7.86(dd，1H)，7.78(d，1H)，4.09(s，3H)。LCMS (method A): [MH] +=161, t R=4.00min.
Midbody J
5-bromo-6-fluoro-1-methyl isophthalic acid H-indazole
Figure BDA0000151397020000561
To 5-bromo-6-fluoro-1H-indazole (4g, 18.60mmol) add in the solution in DMF (20ml) 2-methylpropane-2-potassium alcoholate (2.087g, 18.60mmol).The mixture of gained is stirred 40min.Drip CH 3I (3.17g, 22.32mmol).After the stirred overnight, reaction mixture is used NH 4Cl (aqueous solution) cancellation with the EtOAc extraction, is used NH 4Na is used in Cl (aqueous solution) washing 2SO 4Drying is filtered and vacuum concentration, obtains crude product.(the gradient hexane: EA) purifying crude product obtains faint yellow solid 5-bromo-6-fluoro-1-methyl isophthalic acid H-indazole (1.86g, 42%) with silica gel column chromatography.
Midbody K
4,6-two fluoro-1-methyl isophthalic acid H-indazoles
Figure BDA0000151397020000571
N-methyl-N '-[1-(2,4,6-three fluoro-phenyl)-first-(E)-the fork base]-hydrazine (i)
With 2,4,6-three fluoro-phenyl aldehydes (3g, 18.74mmol) and methyl hydrazine (40% in water, 2.6ml, 18.74mmol) solution in the 20ml absolute ethyl alcohol was in stirring at room 1 hour.Solvent evaporated obtains title compound, is white solid, with its not purified promptly be used for next step (3.95g, 100%).
LCMS (method B): [MH] +=189, t R=2.16min.
4,6-two fluoro-1-methyl isophthalic acid H-indazoles (midbody K)
With N-methyl-N '-[1-(2,4,6-three fluoro-phenyl)-first-(E)-fork base]-hydrazine (3.85g, 20.46mmol) in ST in 210 ℃ of heating 2 hours.After being cooled to room temperature, with black residue be dissolved among the DCM and with the flash chromatography method (EtOAc: purifying hexane 10: 90), obtain title compound, be light yellow crystal (1.926g, 56%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.05(s，1H)；7.16(d，1H)；6.75(t，1H)；3.32(s，3H)。LCMS (method B): [MH] +=169, t R=2.28min.
Midbody L
6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl) methyl) quinoline
Figure BDA0000151397020000572
3-chloro-6-diazanyl pyridazine (i)
With 3, (3g, 20.14mmol) (1g, mixture 20.14mmol) are heated to 80 ℃ and reach 5 hours the 6-dichloro-pyridazine in ST with hydrazine list hydrogenate (hydrazine monohydride).Solvent evaporated is with not purified promptly be used for next step (3.56g, 100%) of crude product.LCMS (method B): [MH] +=145.1, t R=0.57min.
N '-acethydrazide (ii) for (6-chlorine pyridazine-3-yl)-2-(quinoline-6-yl)
To 3-chloro-6-diazanyl pyridazine (3g, 20.75mmol) and 2-(quinoline-6-yl) acetate (4.27g, 22.83mmol) add in the suspension in 200ml DCM DCC (5.14g, 24.90mmol).Solution is spent weekend in stirring at room.Filter out the title compound that contains NSC 30023, be white solid, it promptly is used for next step (8g, 100%) without being further purified.LCMS (method A): [MH] +=314.1, t R=2.85min.
6-((6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl) methyl) quinoline (midbody L)
(the 8g crude product, 25.5mmol) solution in 250mL acetate was in 50 ℃ of heating 5 hours with N '-(6-chlorine pyridazine-3-yl)-2-(quinoline-6-yl) acethydrazide.After reaction was accomplished, solvent evaporated was dissolved among the EtOAc crude product and filtration.Solid mainly is the impurity NSC 30023, and product is dissolved among the EtOAc.Solvent evaporated obtains title compound, is yellow solid (4g, 53%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.82(d，1H)，8.33(d，1H)，8.25(d，1H)，8.0(d，1H)，7.93(s，1H)，7.83(d，1H)，7.53(m，1H)，7.42(d，1H)，4.79(s，2H)。LCMS (method A): [MH] +=296.0, t R=1.88min.
Midbody M
6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-two fluoro-methyl]-quinoline
Figure BDA0000151397020000581
Two fluoro-quinoline-6-base-ETHYLE ACETATE (i)
With Soiodin (4.32g; 28.8mmol), cuprous iodide (I) (137mg; 0.72mmol), 6-bromo-quinoline (3g; 14.4mmol), N, N '-dimethyl--hexanaphthene (0.227ml, 1.44mmol) with two
Figure BDA0000151397020000582
alkane packs in the microwave tube (25mL).Should also use the ZX 21 diaphragm seal by effective nitrogen wash 10min.Reaction mixture was stirred 15 hours in 110 ℃.Make suspension be cooled to room temperature then, pour in the frozen water, extract with DCM.With silicagel column purifying crude product, obtain 6-iodo-quinoline, for a little green solid (3.5g, 92%).
To 6-iodo-quinoline (i) (1.0g, 4mmol) and Cu (0) (559mg, 8.8mmol) add in the suspension in dry DMSO bromo-two fluoro-ETHYLE ACETATE (893mg, 4.4mmol).With reaction mixture at N 2Stirred 15 hours in 55 ℃ down.Pour mixture into K 2CO 3In the solution, extract with EtOAc.Collected organic layer is used MgSO 4Dry.With silicagel column purifying crude product, obtain two fluoro-quinoline-6-base-ETHYLE ACETATE, be red oil (310mg, 30%). 1H-NMR(CDCl 3)δppm1.33(t，J＝7.2，3H)；4.334(q，J＝7.2，2H)；7.52(m，1H)；7.93(m，1H)；8.15(s，1H)；8.20-8.23(m，2H)；9.03(s，1H)。
Two fluoro-quinoline-6-base-acethydrazide (ii)
(836mg 3.33mmol) is dissolved among the MeOH (13ml) with two fluoro-quinoline-6-base-ETHYLE ACETATE.In reaction mixture, add Hydrazine Hydrate 80 (1.5ml, 16.8mmol).Mixture heating up to 45 ℃ is reached 30min, be cooled to room temperature, concentrate, absorb with DCM.Organic layer is used MgSO 4Drying is filtered and vacuum concentration, obtains crude product, and it is used the silicagel column purifying, obtains two fluoro-quinoline-6-base-acethydrazide, be greenish orange look solid (400mg, 51%), 1H-NMR (CDCl 3) δ ppm 3.99 (brs, 2H); 7.51 (m, 1H); 7.92 (m, 1H); 8.15 (s, 1H); 8.20-8.26 (q, 2H); 9.02 (m, 1H).
6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-two fluoro-methyl]-quinoline (midbody M)
With 3, (160mg, 1.07mmol) (254mg 1.07mmol) adds among the n-BuOH (20mL) the 6-dichloro-pyridazine with two fluoro-quinoline-6-base-acethydrazide.Reaction mixture is heated to 130 ℃ reaches 12 hours.Solvent removed in vacuo.Use K 2CO 3Solution and EtOAc extraction crude product.Collected organic layer also concentrates, and obtains solid, and it is used the silicagel column purifying, obtains 6-[(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-two fluoro-methyl]-quinoline, is black solid (190mg, 53%). 1H-NMR(DMSO)δppm?7.62(m，2H)；7.90(m，1H)；8.22(m，1H)；8.35(m，1H)；8.65(m，2H)；9.02(m，1H)。
Midbody N
1-methyl hydrazine methane amide
Figure BDA0000151397020000601
(13g, (24mL 210mmol), drips concentrated hydrochloric acid (18mL) in 0 ℃ then 200mmol) to add the 40% methyl hydrazine aqueous solution in the solution in water (70mL) to Zassol in 0 ℃.The mixture of gained in stirred overnight at room temperature, is filtered then.Concentrated filtrate, dry on lyophilizer, obtain 14g 2-methylamino urea crude product, be white solid.With this crude product with the flash chromatography method (MeOH: DCM=1: 4) purifying, obtain title compound, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?5.92(s，2H)，4.45(s，2H)，2.91(s，3H)。
Midbody O
N-methyl hydrazine methane amide
Figure BDA0000151397020000602
1,3-dimethyl--1-nitrosourea (i)
Go through 1h with sulfuric acid (the 6.0mL vitriol oil, 113mmol) drips of solution in water (100mL) be added to slightly freezing (chilled) 1, the 3-dimethyl urea (10g, 113mmol) and Sodium Nitrite (8.61g is 125mmol) in the solution in water (150mL).Be settled out white solid.After the filtration, filtration cakes torrefaction is also used the tetracol phenixin recrystallization, obtain the 7.8g title compound, be light yellow needle-like crystal solid. 1H-NMR(400MHz，CDCl 3)δppm?6.93(s，1H)，3.21(s，3H)，3.08(d，3H)。N-methyl hydrazine methane amide (midbody O)
In 0 ℃ to 1,3-dimethyl--1-nitrosourea (1.0g, 8.54mmol) add in the solution in water (10mL) single Hydrazine Hydrate 80 (2mL, 64.3mmol).Reaction mixture in stirred overnight at room temperature, is removed and anhydrates.Dried residue on lyophilizer obtains the 810mg title compound, is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?6.87(s，1H)，6.23(s，1H)，3.82(s?br，2H)，2.56(d，3H)。
Midbody P
1-ethyl Hydrazinecarboxamidederivatives
Figure BDA0000151397020000611
Use with the operation identical operations described in midbody N synthetic and prepared this title compound with the ethyl hydrazine. 1H-NMR(400MHz，DMSO-d 6)δppm?5.91(s，2H)，4.37(s，2H)，3.33(q，2H)，1.00(t，3H)。
Embodiment 1
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000612
6-chloro-imidazo [1,2-b] pyridazine-3-yl)-(7-fluoro-quinoline-6-yl)-methyl alcohol (1.1)
(13.27g 57.1mmol) adds EtMgBr (68.5ml, 68.5mmol) solution in the solution in 160mlTHF to 3-bromo-6-chloro-imidazo [1,2-b] pyridazine in room temperature.Reaction mixture is stirred 30min, add 7-fluoro-quinoline-6-formaldehyde (10g, 57.1mmol) suspension in 40ml THF.The mixture of gained in stirring at room 3h, is gone out with the 400ml shrend.After stirring other 1h, through filtering the collecting precipitation thing, with the EtOAc washing, drying under vacuum overnight obtains 13g (yield: title compound 69%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.91(dd，1H)，8.49(d，1H)，8.28(d，1H)，8.24(d，1H)，7.74(d，1H)，7.54(q，1H)，7.51(s，1H)，7.40(d，1H)，6.54(m，2H)。
6-(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl)-7-fluoro-quinoline (1.2)
To 6-chloro-imidazo [1,2-b] pyridazine-3-yl)-(7-fluoro-quinoline-6-yl)-methyl alcohol (9.48g, 28.8mmol) add in the solution in acetate (80mL) phospho acid (50% aqueous solution, 15.73ml, 144mmol) and iodine (18.3g, 72.1mmol).The solution of gained is heated to 110 ℃ and stirred overnight.Under reduced pressure remove and desolvate.With residue diluted with water, its pH is transferred to 8～10 with 6N NaOH solution.Use CH 2Cl 2The solution of extraction gained is used brine wash with the organic layer that merges, and uses anhydrous Na 2SO 4Dry also vacuum concentration.(5% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 5.8g (yield: title compound 64.3%). 1H-NMR(400MHz，CDCl 3)δppm?8.91(dd，1H)，8.14(d，1H)，7.93(d，1H)，7.85(d，1H)，7.75(d，1H)，7.66(s，1H)，7.41(q，1H)，7.09(d，1H)，4.56(s，2H)。LCMS (method B): [MH] +=313, t R=2.48min.
1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone (1.3)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (1.7g, 1.48mmol).Add 6-(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl)-7-fluoro-quinoline (5.8g, 18.55mmol) solution in DMF (150mL).With flask with nitrogen purge three times and add tributyl-(1-oxyethyl group-vinyl)-stannane (6.59ml, 19.47mmol).Temperature is increased to 100 ℃ and stirred overnight.Reaction mixture is cooled to room temperature, adds 20ml 3N HCl, mixture is stirred other 2h.Add entry, use the EtOAc extraction product then, use Na 2SO 4Dry and under reduced pressure concentrated.With column chromatography purifying resistates, (yield: title compound 79%) is the deep yellow solid to obtain 4.8g. 1H-NMR(400MHz，MeOH-d 4)δppm?8.82(dd，1H)，8.31(d，1H)，8.10(d，1H)，7.98(d，1H)，7.85(s，1H)，7.78(d，1H)，7.72(d，1H)，7.50(q，1H)，4.72(s，2H)，2.68(S，3H)。LCMS (method A): [MH] +=321, t R=5.07min.
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 1)
To 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone (320mg, 1mmol) add in the solution in methyl alcohol (30mL) semicarbazide hydrochloride (334mg, 3.0mmol).In reaction mixture, drip triethylamine so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Through filtering collecting precipitation thing and dry with vacuum pump, (yield: title compound 66%) is white solid to obtain 250mg. 1H-NMR?400MHz，DMSO-d 6)δppm?9.69(s，1H)，8.85(dd，1H)，8.30(d，1H)，8.21(d，1H)，7.98(d，1H)，7.94(d，1H)，7.77(d，1H)，7.66(s，1H)，7.47(q，1H)，6.73(b，2H)，4.56(s，2H)，2.23(s，3H)。LCMS (method A): [MH] +=378, t R=4.64min.
Embodiment 2
(E)-6-((6-(1-(2-ethyl hydrazono-) ethyl) imidazo [1,2-b] pyridazine-3-yl) methyl)-7-fluorine quinoline
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 32% by ethyl hydrazine and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，MeOH-d 4)δppm?8.81(dd，1H)，8.27(d，1H)，7.92(d，1H)，7.88(d，1H)，7.78(d，1H)，7.69(d，1H)，7.54(s，1H)，7.47(q，1H)，4.59(s，2H)，3.38(q，2H)，2.13(s，3H)，1.22(t，3H)。LCMS (method A): [MH] +=363, t R=5.32min.
Embodiment 3
(E)-N '-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-acethydrazide
Be similar to the synthetic of embodiment 1 and prepared title compound by acethydrazide and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone, yield 75% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?8.86(d，1H)，8.83(d，1H)，8.07(d，1H)，7.95(d，1H)，7.79(m，2H)，7.70(s，1H)，7.47(q，1H)，4.58(s，2H)，2.28(s，3H)。
LCMS (method A): [MH] +=377, t R=4.83min.
Embodiment 4
(E)-7-fluoro-6-((6-(1-(2-phenyl hydrazono-) ethyl) imidazo [1,2-b] pyridazine-3-yl) methyl)-quinoline
Figure BDA0000151397020000633
Be similar to the synthetic of embodiment 1 and prepared title compound by phenyl hydrazine and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone, yield 32% is yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.78(s，1H)，8.86(dd，1H)，8.32(d，1H)，7.98(m，3H)，7.78(d，1H)，7.61(s，1H)，7.47(q，1H)，7.30(m，4H)，6.83(t，1H)，4.57(s，2H)，2.31(s，3H)。LCMS (method C): [MH] +=411, t R=4.57min.
Embodiment 5
(E)-7-fluoro-6-((6-(1-(2-(pyridine-2-yl) hydrazono-) ethyl) imidazo [1,2-b] pyridazine-3-yl) methyl) quinoline
Figure BDA0000151397020000641
Be similar to the synthetic of embodiment 1 and prepared title compound by pyridine-2-base-hydrazine and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone, yield 48% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?10.27(s，1H)，8.86(dd，1H)，8.31(d，1H)，8.19(d，1H)，7.97(m，3H)，7.78(d，1H)，7.70(t，1H)，7.65(s，1H)，7.47(q，1H)，7.40(d，1H)，6.87(dd，1H)，4.58(s，2H)，2.36(s，3H)。LCMS (method A): [MH] +=412, t R=4.78min.
Embodiment 6
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-N-phenyl hydrazine methane amide
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 36% by N-phenyl hydrazine methane amide and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?10.13(s，1H)，9.06(s，1H)，8.86(dd，1H)，8.30(t，2H)，8.06(d，1H)，7.96(d，1H)，7.78(d，1H)，7.69(s，1H)，7.60(d，2H)，7.48(q，1H)，7.31(t，2H)，7.04(t，1H)，4.58(s，2H)，2.32(s，3H)。LCMS (method C): [MH] +=454, t R=3.89min.
Embodiment 7
(E)-N-(4-chloro-phenyl-)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Be similar to embodiment 1 synthetic by N-right-chloro-phenyl-Hydrazinecarboxamidederivatives and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone prepared title compound. 1H-NMR(400MHz，DMSO-d 6)δppm?10.20(s，1H)，9.18(s，1H)，8.86(dd，1H)，8.31(m，2H)，8.07(d，1H)，7.96(d，1H)，7.78(d，1H)，7.67(m，3H)，7.48(q，1H)，7.36(d，2H)，4.58(s，2H)，2.32(s，3H)。LCMS (method C): [MH] +=489, t R=4.35min.
Embodiment 8
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-1-methyl hydrazine methane amide
Figure BDA0000151397020000652
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 21% by 1-methyl hydrazine methane amide and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?8.86(dd，1H)，8.31(d，1H)，8.05(s，2H)，7.97(d，1H)，7.77(d，1H)，7.72(s，1H)，7.47(q，1H)，6.54(s，2H)，4.58(s，2H)，3.19(s，3H)，2.37(s，3H)。LCMS (method A): [MH] +=392, t R=4.76min.
Embodiment 9
(E)-and 2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-N, 1-dimethylhydrazine methane amide
Figure BDA0000151397020000653
Be similar to the synthetic by N of embodiment 1,1-dimethylhydrazine methane amide and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone has prepared title compound, yield 21%.
1H-NMR(400MHz，DMSO-d 6)δppm?8.86(dd，1H)，8.31(d，1H)，8.06(m，2H)，7.97(d，1H)，7.77(d，1H)，7.73(s，1H)，7.47(q，1H)，6.90(q，1H)，4.59(s，2H)，3.19(s，3H)，2.68(d，3H)，2.37(s，3H)。LCMS (method B): [MH] +=406, t R=2.27min.
Embodiment 10
(E)-3-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine-amino)
Figure BDA0000151397020000661
azoles alkane-2-ketone
Figure BDA0000151397020000662
Be similar to the synthetic of embodiment 1 by amino
Figure BDA0000151397020000663
azoles alkane-2-ketone of 3-and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1; 2-b] pyridazine-6-yl]-ethyl ketone prepared title compound, yield 24%. 1H-NMR(400MHz，CDCl 3)δppm?8.85(dd，1H)，8.02(d，1H)，7.88(m，2H)，7.71(m，3H)，7.33(q，1H)，4.58(s，2H)，4.51(t，2H)，4.01(t，2H)，2.49(s，3H)。LCMS (method A): [MH] +=405, t R=4.76min.
Embodiment 11
(E)-and 1-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine-amino) imidazolidine-2, the 4-diketone
Figure BDA0000151397020000664
Be similar to the synthetic by 1-aminooimidazole alkane-2 of embodiment 1,4-dione hydrochloride and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone has prepared title compound, yield 39%. 1H-NMR(400MHz，DMSO-d 6)δppm?11.39(s，1H)，8.91(dd，1H)，8.40(d，1H)，8.24(d，1H)，8.04(d，1H)，7.94(m，2H)，7.82(d，1H)，7.55(q，1H)，4.64(s，2H)，4.50(s，2H)，2.40(s，3H)。LCMS (method A): [MH] +=418, t R=4.62min.
Embodiment 12
(E)-2-(2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-diazanyl) benzo [d]
Figure BDA0000151397020000671
azoles
Figure BDA0000151397020000672
Be similar to the synthetic of embodiment 1 by 2-diazanyl benzo [d]
Figure BDA0000151397020000673
azoles and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1; 2-b] pyridazine-6-yl]-ethyl ketone prepared title compound, yield 74%. 1H-NMR(400MHz，DMSO-d 6)δppm?11.8-11.5(m，1H)，8.87(dd，1H)，8.4-7.9(m，4)，7.8-7.6(m，2H)，7.6-7.1(m，5H)，4.58(s，2H)，2.49(s，3H)。LCMS (method C): [MH] +=452, t R=4.42min.
Embodiment 13
(E)-N '-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-methylsulfonyl hydrazine
Figure BDA0000151397020000674
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 60% by methylsulfonyl hydrazine and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?10.63(s，1H)，8.85(dd，1H)，8.30(d，1H)，8.09(d，1H)，7.94(d，1H)，7.75(m，3H)，7.47(q，1H)，4.58(s，2H)，3.10(s，3H)，2.26(s，3H)。LCMS (method A): [MH] +=413, t R=4.57min.
Embodiment 14
(E)-N-ethyl-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) hydrazine thion acid amides (carbothioamide)
Figure BDA0000151397020000681
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 53% by N-ethyl hydrazine thion acid amides and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，MeOH-d 4)δppm?8.83(d，1H)，8.30(d，1H)，8.24(d，1H)，7.93(m，2H)，7.69(m，2H)，7.48(q，1H)，4.67(s，2H)，3.74(q，2H)，2.39(s，3H)，1.26(t，3H)。LCMS (method A): [MH] +=422, t R=5.43min.
Embodiment 15
(E)-N-benzyl-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) hydrazine thion acid amides
Figure BDA0000151397020000682
Be similar to the synthetic of embodiment 1 and prepared title compound, yield 80% by N-benzyl hydrazine thion acid amides and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?10.58(s，1H)，9.30(t，1H)，8.86(dd，1H)，8.30(m，2H)，8.05(d，1H)，7.95(d，1H)，7.77(d，1H)，7.69(s，1H)，7.47(q，1H)，7.32(m，4H)，7.23(m，1H)，4.89(d，2H)，4.58(s，2H)，2.39(s，3H)。LCMS (method C): [MH] +=484, t R=4.18min.
Embodiment 16
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-hydrazine thion acid amides
Figure BDA0000151397020000683
Be similar to the synthetic of embodiment 1 and prepared title compound by hydrazine thion amide hydrochloride and 1-[3-(7-fluoro-quinoline-6-ylmethyl)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone, yield 60% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?10.53(s，1H)，8.88(dd，1H)，8.53(s，1H)，8.47(d，1H)，8.34(m，2H)，8.10(d，1H)，7.99(d，1H)，7.85(s，1H)，7.79(d，1H)，7.50(q，1H)，4.59(s，2H)，2.34(s，3H)。LCMS (method A): [MH] +=394, t R=4.91min.
Embodiment 17
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl-d) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000691
6-(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl-d)-7-fluoro-quinoline (17.1)
In the pipe of sealing, add (6-chloro-imidazo [1,2-b] pyridazine-3-yl)-(7-fluoro-quinoline-6-yl)-methyl alcohol (150mg, 0.46mmol), triethyl silicane-d (0.5mL), trifluoroacetic acid-d (0.5mL) and 1.5ml methylene dichloride.Reaction mixture was stirred 5 days in 40 ℃.Then with the cancellation of reaction mixture water and use NaHCO 3The solution neutralization.Use CH 2Cl 2Extraction product is used brine wash with the organic layer that merges, and uses Na 2SO 4Dry and under reduced pressure concentrated.With column chromatography purifying resistates, obtain title compound.LCMS (method B): [MH] +=314, t R=2.39min.
1-[3-(7-fluoro-quinoline-6-ylmethyl-d)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone (17.2)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (21mg, 0.018mmol).(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl-d)-7-fluoro-quinoline is at CH to add 6- 2Cl 2In solution (5mL).With system with nitrogen purge three times, add tributyl-(1-oxyethyl group-vinyl)-stannane (0.063mL, 0.19mmol).Temperature is increased to 100 ℃ and stirred overnight.Reaction mixture is cooled to room temperature, adds 5mL 3N HCl, mixture is stirred other 2h.Add entry, use the EtOAc extraction product, use Na 2SO 4Dry and under reduced pressure concentrated.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain title compound, be yellow solid.LCMS (method B): [MH] +=322, t R=2.24min.
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl-d) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 17)
In 1-[3-(7-fluoro-quinoline-6-ylmethyl-d)-imidazo [1,2-b] pyridazine-6-yl]-solution (15mL) of ethyl ketone in methyl alcohol, add carbamylhydrazine hydrochloride (27mg, 0.25mmol).Drip triethylamine so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Through filtering the collecting precipitation thing, dry with vacuum pump, obtain title compound, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.70(s，1H)，8.86(dd，1H)，8.30(d，1H)，8.21(d，1H)，7.96(m，2H)，7.77(d，1H)，7.66(s，1H)，7.47(q，1H)，6.71(b，2H)，4.54(s，1H)，2.23(s，3H)。
LCMS (method A): [MH] +=379, t R=4.25min.
Embodiment 18
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl-d2) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000701
(6-chlorine imidazo [1,2-b] pyridazine-3-yl) (7-fluorine quinoline-6-yl) ketone (18.1)
To (6-chloro-imidazo [1; 2-b] pyridazine-3-yl)-(1.8g 5.48mmol) adds 2-iodoxybenzene formic acid (8.52g, 45% to (7-fluoro-quinoline-6-yl)-methyl alcohol in the suspension in acetone (200mL); 13.69mmol), reaction mixture was stirred 1 day down in refluxing.Under reduced pressure remove and desolvate, resistates is dissolved in the 200mL water.With the alkalization of 3N NaOH solution, the collecting precipitation thing is used water washing with solution, and dry with vacuum drying oven, (yield: title compound 95%) is gray solid to obtain 1.7g. 1H-NMR(400MHz，DMSO-d 6)δppm?9.04(dd，1H)，8.56(d，1H)，8.47(m，2H)，8.41(s，1H)，7.92(d，1H)，7.75(d，1H)，7.64(q，1H)。LCMS (method B): [MH] +=327, t R=2.03min.
6-(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl-d2)-7-fluoro-quinoline (18.2)
In microwave tube, add (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (7-fluorine quinoline-6-yl) ketone (90mg, 0.28mmol), triethyl silicane-d (0.7mL), trifluoroacetic acid-d (0.7ml) and 2ml 1, the 2-ethylene dichloride.Reaction mixture is stirred 5h in 120 ℃ in microwave reactor.With the cancellation of reaction mixture water and use NaHCO 3The solution neutralization.Use CH 2Cl 2The mixture of extraction gained is used brine wash with the organic layer that merges, and uses Na 2SO 4Dry and under reduced pressure concentrated.(5% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, (yield: title compound 20%) is yellow solid to obtain 30mg. 1H-NMR(400MHz，CDCl 3)δppm?8.88(dd，1H)，8.09(d，1H)，7.91(d，1H)，7.77(d，1H)，7.72(d，1H)，7.64(s，1H)，7.36(q，1H)，7.05(d，1H)。LCMS (method B): [MH] +=315, t R=2.39min.
1-[3-(7-fluoro-quinoline-6-ylmethyl-d2)-imidazo [1,2-b] pyridazine-6-yl]-ethyl ketone (18.3)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (21mg, 0.018mmol).(6-chloro-imidazo [1,2-b] pyridazine-3-ylmethyl-d2)-7-fluoro-quinoline is at CH to add 6- 2Cl 2In solution (10mL).With system with nitrogen purge three times, add then tributyl-(1-oxyethyl group-vinyl)-stannane (0.063ml, 0.19mmol).Temperature is increased to 100 ℃ and stirred overnight.Then reaction mixture is cooled to room temperature, adds 5mL 3N HCl, mixture is stirred other 2h.Add entry, extract mixture with EtOAc then, use Na 2SO 4Dry and under reduced pressure concentrated.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain title compound, be the deep yellow solid.LCMS (method B): [MH] +=323, t R=2.24min.
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl-d2) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 18)
In 1-[3-(7-fluoro-quinoline-6-ylmethyl-d2)-imidazo [1,2-b] pyridazine-6-yl]-solution (10mL) of ethyl ketone in methyl alcohol, add carbamylhydrazine hydrochloride (29mg, 0.25mmol).Drip triethylamine then so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Through filtering the collecting precipitation thing, dry with vacuum pump, obtain title compound, be faint yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.70(s，1H)，8.86(s，1H)，8.30(d，1H)，8.21(d，1H)，7.96(m，2H)，7.77(d，1H)，7.66(s，1H)，7.47(q，1H)，6.73(b，2H)，2.23(s，3H)。LCMS (method A): [MH] +=380, t R=4.18min.
Embodiment 19
(E)-2-(1-(3-(quinoline-6-ylmethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-hydrazine-methane amide
Figure BDA0000151397020000721
Be similar to the synthetic title compound that prepared of embodiment 1, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.70(s，1H)，8.83(dd，1H)，8.29(d，1H)，8.19(d，1H)，7.95(m，3H)，7.75(d，1H)，7.68(s，1H)，7.47(q，1H)，6.74(b，2H)，4.53(s，2H)，2.25(s，3H)。LCMS (method A): [MH] +=360, t R=3.84min.
Embodiment 20
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000722
Be similar to the synthetic title compound that prepared of embodiment 1, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.69(s，1H)，8.96(d，1H)，8.46(d，1H)，8.19(d，1H)，7.95(d，1H)，7.70(d，1H)，7.63(s，1H)，7.60(q，1H)，6.67(b，2H)，4.57(s，2H)，2.24(s，3H)。LCMS (method A): [MH] +=396, t R=5.08min.
Embodiment 21
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-1-methyl hydrazine methane amide
Figure BDA0000151397020000731
Be similar to the synthetic title compound that prepared of embodiment 8. 1H-NMR(400MHz，DMSO-d 6)δppm?8.96(d，1H)，8.47(d，1H)，8.01(s，2H)，7.69(m，2H)，7.61(q，1H)，6.54(s，2H)，4.60(s，2H)，3.19(s，3H)，2.37(s，3H)。LCMS (method A): [MH] +=410, t R=5.19min.
Embodiment 22
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000732
1-(3-((7-fluorine quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (22.1)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (176mg, 0.15mmol).(500mg is 1.52mmol) at CH for (7-fluorine quinoline-6-yl) methyl alcohol to add (6-chlorine imidazo [1,2-b] pyridazine-3-yl) 2Cl 2Solution (20mL), with system with nitrogen purge three times, add tributyl-(1-oxyethyl group-vinyl)-stannane (0.54ml, 1.59mmol).Temperature is increased to 100 ℃ and stirred overnight.Reaction mixture is cooled to room temperature, adds 3N HCl, mixture is stirred other 4h.Add entry, extract mixture with EtOAc then, use Na 2SO 4Dry and under reduced pressure concentrated.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 500mg (yield: title compound 88%).LCMS (method B): [MH] +=337, t R=1.88min.
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 22)
To 1-(3-((7-fluorine quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (100mg, 0.27mmol) add in the solution in methyl alcohol (15mL) carbamylhydrazine hydrochloride (45mg, 0.41mmol).Drip triethylamine so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Through filtering collecting precipitation thing and dry with vacuum pump, (yield: title compound 47%) is white solid to obtain 50mg. 1H-NMR(400MHz，DMSO-d 6)δppm?9.68(s，1H)，8.89(dd，1H)，8.45(d，1H)，8.25(m，2H)，7.99(d，1H)，7.72(d，1H)，7.57(s，1H)，7.52(q，1H)，6.67(b，2H)，6.62(s，1H)，6.47(b，1H)，2.19(s，3H)。LCMS (method A): [MH] +=394, t R=3.95min.
Embodiment 23
(E)-2-(1-(3-(hydroxyl (quinoline-6-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000741
Be similar to the synthetic title compound that prepared of embodiment 22, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.69(s，1H)，8.86(dd，1H)，8.37(d，1H)，8.20(d，1H)，8.12(s，1H)，7.98(d，2H)，7.85(d，1H)，7.65(s，1H)，7.52(q，1H)，6.70(b，2H)，6.44(s，1H)，6.34(b，1H)，2.24(s，3H)。LCMS (method A): [MH] +=376, t R=3.25min.
Embodiment 24
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-1-methyl hydrazine methane amide
Figure BDA0000151397020000742
Be similar to the synthetic title compound that prepared of embodiment 22. 1H-NMR(400MHz，DMSO-d 6)δppm?8.88(d，1H)，8.46(d，1H)，8.30(d，1H)，8.04(s，2H)，7.72(d，1H)，7.61(s，1H)，7.52(q，1H)，6.64(d，1H)，6.55(s，2H)，6.51(d，1H)，3.19(s，3H)，2.33(s，3H)。LCMS (method A): [MH] +=408, t R=4.16min.
Embodiment 25
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000751
Be similar to the synthetic title compound that prepared of embodiment 22, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.63(s，1H)，8.97(dd，1H)，8.47(d，1H)，8.16(d，1H)，7.96(d，1H)，7.84(s，1H)，7.66(d，1H)，7.60(q，1H)，6.75(d，1H)，6.70(b，2H)，6.65(d，1H)，2.06(s，3H)。LCMS (method A): [MH] +=412, t R=4.09min.
Embodiment 26
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) (hydroxyl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-1-methyl hydrazine methane amide
Be similar to the synthetic title compound that prepared of embodiment 22. 1H-NMR(400MHz，DMSO-d 6)δppm?8.97(d，1H)，8.48(d，1H)，8.00(m，2H)，7.90(s，1H)，7.66(d，1H)，7.60(q，1H)，6.74(m，2H)，6.51(s，2H)，3.14(s，3H)，2.19(s，3H)。LCMS (method A): [MH] +=426, t R=4.29min.
Embodiment 27
(E)-2-(1-(3-(1-(7-fluorine quinoline-6-yl)-1-hydroxyethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl)-1-(7-fluorine quinoline-6-yl) ethanol (27.1)
To (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (7-fluorine quinoline-6-yl) ketone (2.93g, 6.73mmol) add in the solution in THF (80mL) MeMgI solution (4.48mL, 13.45mmol).The solution of gained is stirred 5h under refluxing.Then reaction mixture is cooled to room temperature, NH is used in the water cancellation 4The Cl solution washing is also used CH 2Cl 2Extraction.The organic layer that merges is used Na 2SO 4Dry and under reduced pressure concentrated, (yield: title compound 95%) promptly is used for next step with it without being further purified to obtain 2.2g.LCMS (method B): [MH] +=343, t R=2.05min.
1-(3-(1-(7-fluorine quinoline-6-yl)-1-hydroxyethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (27.2)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (51mg, 0.044mmol).Add 1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl)-1-(7-fluorine quinoline-6-yl) ethanol (150mg, 0.44mmol) solution in DMF (10mL).With system with nitrogen purge three times, add tributyl-(1-oxyethyl group-vinyl)-stannane (0.16ml, 0.46mmol).Temperature is increased to 100 ℃ and stirred overnight.Reaction mixture is cooled to room temperature, adds 3N HCl and mixture is stirred other 4h.Add entry, extract mixture with EtOAc then, use Na 2SO 4Dry and under reduced pressure concentrated.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 70mg (yield: title compound 41%).LCMS (method B): [MH] +=351, t R=2.01min.
(E)-2-(1-(3-(1-(7-fluorine quinoline-6-yl)-1-hydroxyethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 27)
To 1-(3-(1-(7-fluorine quinoline-6-yl)-1-hydroxyethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (35mg, 0.09mmol) add in the solution in methyl alcohol (20mL) carbamylhydrazine hydrochloride (20mg, 0.18mmol).Drip triethylamine so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Enriching soln under reduced pressure, (3%-50%MeOH is at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 23mg (yield: title compound 62%). 1H-NMR(400MHz，DMSO-d 6)δppm?9.47(s，1H)，8.87(d，1H)，8.52(m，2H)，8.06(d，1H)，7.92(d，1H)，7.85(s，1H)，7.54(m，2H)，6.62(b，2H)，6.24(s，1H)，2.13(s，3H)，1.53(s，3H)。LCMS (method A): [MH] +=408, t R=4.03min.
Embodiment 28
(E)-2-(1-(3-(1-hydroxyl-1-(quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000771
Be similar to the synthetic title compound that prepared of embodiment 27, be yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.52(s，1H)，8.82(d，1H)，8.33(d，1H)，8.09(m，2H)，7.91(m，3H)，7.73(d，1H)，7.47(q，1H)，6.64(b，2H)，6.60(s，1H)，2.12(s，3H)，1.85(s，3H)。LCMS (method B): [MH] +=390, t R=1.55min.
Embodiment 29
(E)-2-(1-(3-(1-(7-fluorine quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000772
6-(1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl) ethyl)-7-fluorine quinoline (29.1)
To 1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl)-1-(7-fluorine quinoline-6-yl) ethanol (420mg, 1.10mmol) add in the solution in acetate (20mL) phospho acid (50% aqueous solution, 0.60ml, 5.51mmol) and iodine (700mg, 2.76mmol).The solution of gained in 110 ℃ of heated overnight, is removed and desolvates.The dilute with water resistates transfers to 8～10 with 6N NaOH solution with pH.Use CH then 2Cl 2The extraction mixture is used brine wash, uses anhydrous Na 2SO 4Dry also vacuum concentration.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 260mg (yield: title compound 72%).LCMS (method B): [MH] +=327, t R=2.52min.
1-(3-(1-(7-fluorine quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (29.2)
Under nitrogen, and four-(the triphenyl phosphine)-palladium of in flask, packing into (46mg, 0.040mmol).Add 6-(1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl) ethyl)-7-fluorine quinoline (130mg, 0.40mmol) solution in DMF (5mL).With system with nitrogen purge three times, add tributyl-(1-oxyethyl group-vinyl)-stannane (0.14mL, 0.42mmol).Temperature is increased to 100 ℃ and stir 2h.Then reaction mixture is cooled to room temperature, adds 3N HCl and mixture is stirred other 4h.Add entry, then mixture is extracted with EtOAc, use Na 2SO 4Dry and under reduced pressure concentrated.(3% to 10%MeOH at CH with column chromatography 2Cl 2In solution) the purifying resistates, obtain 120mg (yield: 90) title compound.LCMS (method B): [MH] +=335, t R=2.41min.
(E)-2-(1-(3-(1-(7-fluorine quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 29)
To 1-(3-(1-(7-fluorine quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (60mg, 0.18mmol) add in the solution in methyl alcohol (10ml) carbamylhydrazine hydrochloride (40mg, 0.36mmol).Drip triethylamine so that pH is transferred to 5～6.With reaction mixture in stirred overnight at room temperature.Through filtering collecting precipitation thing and dry with vacuum pump, (yield: title compound 54%) is white solid to obtain 38mg. 1H-NMR(400MHz，DMSO-d 6)δppm?9.62(s，1H)，8.84(d，1H)，8.26(d，1H)，8.15(d，1H)，7.96(d，1H)，7.77(m，3H)，7.44(q，1H)，6.69(b，2H)，5.03(t，1H)，2.07(s，3H)，1.83(d，3H)。LCMS (method A): [MH] +=392, t R=4.88min.
Embodiment 30 and 30*
(E)-2-(1-(3-(1-(quinoline-6-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) hydrazine-methane amide
Figure BDA0000151397020000781
Embodiment 30 and embodiment 30*
Be similar to the synthetic title compound for preparing the racemic mixture form of embodiment 29, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.65(s，1H)，8.82(dd，1H)，8.27(d，1H)，8.15(d，1H)，7.93(t，2H)，7.88(d，1H)，7.80(s，1H)，7.74(dd，1H)，7.47(q，1H)，6.72(b，2H)，4.81(q，1H)，2.13(s，3H)，1.82(d，3H)。LCMS (method A): [MH] +=374, t R=4.37min.Chiral separation (method F) provides the compound embodiment 30 and the 30* of enantiomer-pure.
Embodiment 31
(E)-2-(1-(3-(1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000791
1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethanol (31.1)
To in-78 ℃ 4,6-two fluoro-1-methyl isophthalic acid H-indazoles (600mg, 3.57mmol) add in the solution in the anhydrous THF of 20mL n-BuLi (solution of 1.6M in hexane, 2.56mL, 4.1mmol).Solution was stirred 1 hour under this temperature, drip 1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-ethyl ketone (698mg, 3.57mmol) solution in the anhydrous THF of 10mL in-78 ℃ then.The solution of gained was stirred 3 hours under this temperature, slowly be warmed to room temperature and stirred overnight.With the cancellation of reaction mixture water, with EtOAc extraction three times.Merge organic layer, use brine wash, use Na 2SO 4Dry.With flash chromatography method (CH 2Cl 2: purifying crude product MeOH 95: 5), obtain title compound, be yellow oil (530mg, 41%). 1H-NMR(400MHz，CDCl 3)δppm8.05(d，1H)，8.0(s，1H)，7.85(s，1H)，7.1(d，1H)，6.85(d，1H)，4.0(s，3H)，2.3(s，3H)。LCMS (method B): [MH] +=363.9, t R=2.15min.
6-chloro-3-[1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethyl]-imidazo [1,2-b] pyridazine (31.2)
With 1-(6-chloro-imidazo [1; 2-b] pyridazine-3-yl)-1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethanol (530mg, 1.457mmol), iodine (925mg; 3.64mmol) and phospho acid (50%, 0.556mL) solution in 20mL acetate in 110 ℃ the heating 2 hours.Solvent evaporated is dissolved in resistates in the water, uses saturated NaHCO 3CH is used in the solution neutralization 2Cl 2Extract three times.Merge organic layer, use brine wash, use Na 2SO 4Dry.Solvent evaporated with flash chromatography method (hexane: EtOAc 1: 2) purifying crude product, obtains title compound then, is faint yellow solid (320mg, 63.2%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.03(s，1H)，8.0(d，1H)，7.8(s，1H)，7.23(d，1H)，7.19(d，1H)，5.1(q，1H)，4.0(s，3H)，1.92(d，3H)。LCMS (method B): [MH] +=347.9, t R=2.69min.
3-[1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethyl]-6-(1-oxyethyl group-vinyl)-imidazo [1,2-b] pyridazine (31.3)
With 6-chloro-3-[1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethyl]-imidazo [1,2-b] pyridazine (80mg, 0.23mmol) and tributyl (1-vinyl ethyl ether base) stannane (0.234mL, 0.69mmol) solution in 15mL DMF is used N 2Purify 30min, add then four-(triphenyl phosphine)-palladium (80mg, 0.069mmol), with solution in 95 ℃ of heated overnight.Water cancellation reaction then is with EtOAc extraction three times.Merge organic layer,, use Na with KF solution and brine wash 2SO 4Dry.Solvent evaporated promptly is used for next step with crude product (80mg, 90%) without being further purified.LCMS (method C): [MH] +384.0, t R=4.67min
1-(3-(1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (31.4)
2mL 3N HCl solution is joined in 3-[1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls)-ethyl]-6-(1-oxyethyl group-vinyl)-solution of imidazo [1,2-b] pyridazine in 10ml MeOH.Reaction soln in stirring at room 3 hours, is used saturated NaHCO then 3The solution neutralization.Solvent evaporated is with chromatography (CH 2Cl 2: purifying resistates MeOH 10: 1), obtain title compound, be yellow solid (30mg, 41%).LCMS (method C): [MH] +355.9, t R=3.75min
(E)-2-(1-(3-(1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 31)
(22mg, 0.062mmol) (16mg, 0.14mmol) solution in 8mLMeOH is in stirred overnight at room temperature with the Hydrazinecarboxamidederivatives hydrochloride for ethyl ketone with 1-(3-(1-(4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) ethyl) imidazo [1,2-b] pyridazine-6-yl).Then solution is used saturated NaHCO 3The solution neutralization extracts with EtOAc.Merge organic layer and use brine wash, use Na 2SO 4Dry.Solvent evaporated (is used 0.05%NH with HPLC purifying crude product 4OH makes it to be alkalescence), obtain title compound, be white solid (10mg, 35%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.10(d，1H)，8.02(s，1H)，7.89(d，1H)，7.79(m，1H)，7.15(d，1H)，5.15(q，1H)，3.99(s，3H)，2.18(s，3H)，1.96(d，3H)。LCMS (method B): [MH] +=413.0, t R=2.41min.
Embodiment 32
(E)-2-(1-(3-((4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000811
(6-chlorine imidazo [1,2-b] pyridazine-3-yl) (4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl alcohol (32.1)
Use with the operation identical operations described in compound 31.1 synthetic by midbody 4; (70mg is 0.416mmol) with 6-chlorine imidazo [1,2-b] pyridazine-3-formaldehyde (76mg for 6-two fluoro-1-methyl isophthalic acid H-indazoles; 0.416mmol) synthesized title compound; Be yellow solid (60mg, 0.172mmol, 41%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.08(s，1H)，8.03(d，1H)，7.85(s，1H)，7.26(q，2H)，6.76(s，1H)，4.03(s，3H)。LCMS (method B): [MH] +=349.9, t R=2.12min.
6-chloro-3-((4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl) imidazo [1,2-b] pyridazine (32.2)
Use with the operation identical operations described in compound 31.2 synthetic by (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl alcohol (500mg; 1.43mmol), iodine (907mg; 3.57mmol) and phospho acid (50%, 0.55mL) synthesized title compound, be faint yellow solid (370mg; 1.109mmol, 78%). 1H-NMR(400MHz，MeOH-d 4)δppm8.07(s，1H)，8.01(d，1H)，7.44(s，1H)，7.29(d，1H)，7.27(d，1H)，4.46(s，2H)，4.04(s，3H)。LCMS (method B): [MH] +=333.9, t R=2.68min.
1-(3-((4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (32.3)
Use with the operation identical operations described in compound 31.4 synthetic by 6-chloro-3-((4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl) imidazo [1,2-b] pyridazine (360mg; 1.079mmol), tributyl (1-vinyl ethyl ether base) stannane (1.095ml; 3.24mmol) and four-(triphenyl phosphine)-palladium (374mg 0.324mmol) has synthesized title compound, is faint yellow solid (350mg; 0.769mmol, 71.3%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.09(s，1H)，8.07(s，1H)，7.78(d，1H)，7.71(s，1H)，7.26(d，1H)，4.59(s，2H)，4.02(s，3H)，2.74(s，3H)。LCMS (method B): [MH] +=342.0, t R=2.39min.
(E)-2-(1-(3-((4,6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 32)
(3-((4 with 1-; 6-two fluoro-1-methyl isophthalic acid H-indazole-5-yls) imidazo [1,2-b] pyridazine-6-yl methyl)) ethyl ketone (45mg, 0.099mmol; 75% purity) and the Hydrazinecarboxamidederivatives hydrochloride (22mg, 0.198mmol) solution in 10mL MeOH is in stirred overnight at room temperature.Solvent evaporated is dissolved in resistates among a small amount of MeOH.Form throw out, it leached, obtain title compound, for white solid (25mg, 0.062mmol). 1H-NMR (400MHz, DMSO-d 6) δ ppm 9.95 (s, 1H), 8.62 (d, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 8.0 (s, 1H), 7.54 (d, 1H), 6.85 (wide, 2H), 4.48 (s, 2H), 4.0 (s, 3H), 2.3 (s, 3H).LCMS (method B): [MH] +=398.9, t R=2.17min.
Embodiment 33
(E)-2-(1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000821
1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethyl ketone (33.1)
Use with the operation identical operations described in compound 31.4 synthetic by 6-((6-chloro-[1; 2,4] quinoline (500mg difluoromethyl triazolo [4,3-b] pyridazine-3-yl)); 1.507mmol), tributyl (1-vinyl ethyl ether base) stannane (2.55ml, 7.54mmol) and PdCl 2(PPh 3) 2(106mg, 0.151mmol) 1,4-two
Figure BDA0000151397020000822
Synthesized title compound in the alkane, be faint yellow oily thing (180mg, 30%, 80% purity). 1H-NMR(400MHz，MeOH-d 4)δppm?9.17(s，1H)，8.91(d，1H)，8.65(s，1H)，8.43(d，1H)，8.28(q，2H)，7.96(d，1H)，7.92(m，1H)，2.61(s，3H)。LCMS (method B): [MH] +=340.1, t R=2.16min.
(E)-2-(1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 33)
(100mg, 0.295mmol) (44.3mg, 0.589mmol) solution in MeOH is in stirred overnight at room temperature with the Hydrazinecarboxamidederivatives hydrochloride for ethyl ketone with 1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl).Solvent evaporated is dissolved in resistates among a small amount of MeOH.Leach solid and dry, obtain title compound, be white solid (90mg, 75%). 1H-NMR (400MHz, DMSo-d 6) δ ppm 9.90 (s, 1H), 9.06 (d, 1H), 8.62 (d, 1H), 8.49 (m, 2H), 8.34 (d, 1H), 8.20 (d, 1H), 8.03 (d, 1H), 7.70 (m, 1H), 6.82 (wide, 2H), 2.07 (s, 3H).LCMS (method B): [MH] +=397.1, t R=2.08min.
Embodiment 34
(E)-and 1-(1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine is amino) imidazolidine-2, the 4-diketone
Figure BDA0000151397020000831
(20mg, 0.059mmol) with 1-aminooimidazole alkane-2, (13.6mg, solution 0.12mmol) is spent weekend in stirring at room to the 4-diketone in MeOH with 1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethyl ketone.Leach faint yellow solid, obtain title compound (6mg, 0.014mmol).With HPLC purifying filtrating (making it to be acid) with 0.05%TFA, obtain title compound, for tfa salt (8mg, 0.0145mmol).The yield that merges is 48%. 1H-NMR(400MHz，DMSo-d 6)δppm?11.46(s，1H)，9.02(d，1H)，8.55(d，1H)，8.48(s，1H)，8.46(s，1H)，8.18(d，1H)，8.0(s，1H)，7.98(s，1H)，7.65(d，1H)，4.54(s，2H)，2.24(s，3H)。LCMS (method B): [MH] +=437.1, t R=2.06min.
Embodiment 35
(E)-1-(1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine is amino) imidazolidin-2-one
Figure BDA0000151397020000841
(20mg, 0.059mmol) (12mg, 0.12mmol) solution in MeOH is in stirred overnight at room temperature with 1-aminooimidazole alkane-2-ketone for ethyl ketone with 1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl).Solvent evaporated is with flash chromatography method (CH 2Cl 2: purifying crude product MeOH 9: 1), obtain title compound, be white solid (8mg, 32%). 1H-NMR(400MHz，MeOH-d 4)δppm?8.98(s，1H)，8.52(d，1H)，8.43(s，1H)，8.26(d，2H)，8.19(m，1H)，8.06(d，1H)，7.66(d，1H)，3.55(t，2H)，3.38(t，2H)，2.30(s，3H)。LCMS (method A): [MH] +=423.0, t R=4.63min.
Embodiment 36
(E)-N '-(1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-2-morpholino acethydrazide
Figure BDA0000151397020000842
(25mg, 0.074mmol) (12mg 0.075mmol) is dissolved among the MeOH, and the pH of reaction soln is transferred to 5 with 2-morpholino acethydrazide with 1-(3-(difluoro (quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethyl ketone.Then with solution in 45 ℃ stir 3 little, the time.Solvent evaporated with HPLC purifying crude product (in synthetic free alkali), obtains title compound, is white solid (18mg, 50%). 1H-NMR(400MHz，DMSO-d 6)δppm?9.02(s，1H)，8.55(d，1H)，8.43(d，2H)，8.17(d，1H)，8.01(m，2H)，7.65(d，1H)，3.59(m，4H)，2.13(m，4H)。LCMS (method B): [MH] +=481.1, t R=1.66min.
Embodiment 37
(E)-2-(1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (37)
Figure BDA0000151397020000851
1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethyl ketone (37.1)
Use with the operation identical operations described in compound 31.4 synthetic by 6-((6-chloro-[1,2,4] triazolo [4; 3-b] pyridazine-3-yl) methyl) quinoline (950mg; 3.21mmol), tributyl (1-oxyethyl group-vinyl) stannane (1.142ml, 3.37mmol) (186mg 0.161mmol) has synthesized title compound in DMF with four-(triphenyl phosphine)-palladium; Be faint yellow solid (500mg, 51%).LCMS (method B): [MH] +=304.1, t R=1.71min.
(E)-2-(1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 37)
(35mg, 0.115mmol) (17.32mg, 0.231mmol) solution in MeOH is in stirred overnight at room temperature with the Hydrazinecarboxamidederivatives hydrochloride with 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethyl ketone.Leach solid and dry, obtain title compound, be faint yellow solid (35mg, 84%). 1H-NMR (400MHz, DMSO-d 6) δ ppm 9.90 (s, 1H), 9.10 (d, 1H), 8.79 (d, 1H), 8.37 (d, 1H), 8.17 (m, 3H), 8.03 (d, 1H), 7.83 (m, 1H), 6.85 (wide, 2H), 4.84 (s, 2H), 2.24 (s, 3H).LCMS (method A): [MH] +=361.1, t R=3.58min.
Embodiment 38
(E)-and 1-(1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine is amino)-imidazolidine-2, the 4-diketone
Figure BDA0000151397020000852
Use with the operation identical operations described in embodiment 37 synthetic by 1-(3-(quinoline-6-ylmethyl)-[1; 2,4] ethyl ketone (30mg triazolo [4,3-b] pyridazine-6-yl); 0.1mmol) and 1-aminooimidazole alkane-2; (22.77mg 0.198mmol) has synthesized title compound (20mg, 51%) to the 4-diketone. 1H-NMR(400MHz，DMSO-d 6)δppm?11.44(s，1H)，9.05(d，1H)，8.70(d，1H)，8.32(d，1H)，8.12(d，2H)，7.98(d，1H)，7.87(d，1H)，7.77(m，1H)，4.83(s，2H)，4.54(s，2H)，2.40(s，3H)。LCMS (method B): [MH] +=401.1, t R=1.64min.
Embodiment 39
(E)-1-methyl-2-(1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000861
Use with the operation identical operations described in embodiment 37 synthetic by 1-(3-(quinoline-6-ylmethyl)-[1,2,4] triazolo [4; 3-b] pyridazine-6-yl) ethyl ketone (40mg; 0.132mmol) and 1-methyl hydrazine-methane amide (23.5mg 0.264mmol) has synthesized title compound (27mg, 55%). 1H-NMR(400MHz，DMSO-d 6)δppm?9.06(d，1H)，8.73(d，1H)，8.17(m，4H)，8.00(d，1H)，7.79(m，1H)，6.69(s，2H)，4.82(s，2H)，3.27(s，3H)，2.32(s，3H)。LCMS (method A): [MH] +=375.0, t R=3.79min.
Embodiment 40
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000862
(5,7-two fluoro-quinoline-6-yl)-acethydrazide (40.1)
(1.023g 4.32mmol) adds single Hydrazine Hydrate 80 (2mL) in the solution in ethanol (15mL), mixture is stirred 24h in 30 ℃ to (5,7-two fluoro-quinoline-6-yl)-methyl acetate.Solvent removed in vacuo obtains the 1.024g title compound, is white solid, and it is used without being further purified promptly.
1H-NMR(400MHz，DMSO-d 6)δppm?9.33(s，1H)，8.97(d，1H)，8.46(d，1H)，7.67(d，1H)，7.61(dd，1H)，4.27(s，2H)。LCMS (method B): [MH] +=238, t R=3.24min.(5,7-difluoro-quinoline-6-yl)-methyl acetate is with the method described in the WO2008/144767 the 108th page (midbody 2), uses the 14th page of midbody 12 of WO2008/144767, the method synthetic described in the step 1 then.
6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-5,7-two fluoro-quinoline (40.2)
(1.024g, 4.32mmol) with 3, (0.772g, 5.18mmol) solution in 60mL butane-1-alcohol heats 16h in 135 ℃ to the 6-dichloro-pyridazine in the pipe of sealing with (5,7-two fluoro-quinoline-6-yl)-acethydrazide.Solvent removed in vacuo with flash chromatography method purifying resistates, obtains the 842mg title compound, is gray solid. 1H-NMR(400MHz，DMSO-d 6)δppm?8.96(dd，1H)，8.26(d，1H)，7.60-7.66(m，2H)，7.45(d，1H)，4.81(s，2H)。LCMS (method B): [MH] +=332, t R=4.88min.
6-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-5,7-two fluoro-quinoline (40.3)
With 6-(6-chloro-[1; 2; 4] triazolo [4; 3-b] pyridazine-3-ylmethyl)-5,7-two fluoro-quinoline (58mg, 0.175mmol) two
Figure BDA0000151397020000871
solution in the alkane (5mL) uses purification for argon 1min.(0.2mL 0.53mmol), adds PdCl subsequently to add tributyl-(1-oxyethyl group-vinyl) stannane then 2(PPh 3) 2(14.4mg, 0.021mmol).With reaction mixture with other half a minute of purification for argon.Reaction mixture is stirred 4h in 80-85 ℃; The LC/MS demonstration reacts completely.Reaction mixture is diluted with EtOAc, add the 15mL KF aqueous solution.Extract mixture with EtOAc, use anhydrous Na 2SO 4Drying concentrates, and obtains the title compound bullion, and it is used without being further purified promptly.LCMS (method A): [MH] +=368, t R=5.39min.
1-[3-(5,7-two fluoro-quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl] ethyl ketone (40.4)
(0.2mL 0.6mmol) joins 6-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-5, and (87mg is 0.237mmol) in the solution in HOAc (2mL) for 7-two fluoro-quinoline with the 3N HCl aqueous solution.Reaction mixture is stirred 6h in 40 ℃.The LC/MS demonstration reacts completely.Solvent removed in vacuo is dissolved in resistates among the EtOAc, and neutralization extracts with EtOAc.Organic layer is dry, concentrate and, obtain the 40mg title compound with flash chromatography method purifying, be light yellow solid. 1H-NMR(400MHz，MeOH-d 4)δppm?8.95(dd，1H)，8.56(d，1H)，8.29(d，1H)，7.85(d，1H)，7.60-7.67(m，2H)，4.94(s，2H)，2.67(s，3H)。LCMS (method A): [MH] +=339, t R=4.88min.
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 40)
With 1-[3-(5,7-two fluoro-quinoline-6-ylmethyl)-[1,2; 4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (38mg, 0.112mmol), Urea,amino-(37.5mg; 0.336mmol) and sodium hydrogencarbonate (40mg, 0.67mmol) mixture in methyl alcohol (3mL) stirs 20h in 40 ℃.The LC/MS demonstration reacts completely, and filters suspension.To filtrate and use cold water and methanol wash successively, dry then, obtain 36.3mg (yield 82%) title compound, be white solid. 1H-NMR(400MHz，DMSO-d 6)δppm9.85(s，1H)，8.99(dd，1H)，8.49(d，1H)，8.35(d，1H)，8.18(d，1H)，7.73(d，1H)，7.62(dd，1H)，6.82(s?br，2H)，4.75(s，2H)，2.19(s，3H)。LCMS (method A): [MH] +=397, t R=4.43min.
Embodiment 41
(E)-and 2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-N, 1-dimethylhydrazine methane amide
Figure BDA0000151397020000881
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound. 1H-NMR(400MHz，DMSO-d 6)δppm?8.99(d，1H)，8.49(d，1H)，8.27(d，1H)，8.19(d，1H)，7.74(d，1H)，7.62(dd，1H)，7.03-7.05(m，1H)，4.78(s，2H)，3.26(s，3H)，2.70(d，3H)，2.34(s，3H)。LCMS (method A): [MH] +=425, t R=4.74min.
Embodiment 42
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-1-methyl hydrazine methane amide
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound.
1H-NMR(400MHz，DMSO-d 6)δppm?9.00(dd，1H)，8.50(d，1H)，8.17-8.25(m，2H)，7.75(d，1H)，7.64(dd，1H)，6.70(s，2H)，4.79(s，2H)，3.27(s，3H)，2.35(s，3H)。LCMS (method A): [MH] +=411, t R=4.60min.
Embodiment 43
(E)-2-(1-(3-((5,7-difluoro-quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-1-ethyl Hydrazinecarboxamidederivatives
Figure BDA0000151397020000892
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound.
1H-NMR(400MHz，CDCl 3)δppm?8.95(dd，1H)，8.38(dd，1H)，8.05(d，1H)，7.86(d，1H)，7.64(d，1H)，7.44(dd，1H)，5.42(s?br，2H)，4.84(s，2H)，3.95(q，2H)，2.46(s，3H)，1.18(t，3H)。LCMS (method A): [MH] +=425, t R=4.75min.
Embodiment 44
(E)-((3-((5 for 1-for 3-; 7-difluoro-quinoline-6-yl) methyl)-[1; 2; 4] triazolo [4,3-b] pyridazine-6-yl) ethidine is amino) azoles alkane-2-ketone
Figure BDA0000151397020000894
Use that (3-((5 by amino
Figure BDA0000151397020000895
azoles alkane-2-ketone of 3-and 1-with the operation identical operations described in embodiment 40 synthetic; 7-difluoro-quinoline-6-yl) methyl)-[1; 2; 4] triazolo [4; 3-b] pyridazine-6-yl) ethyl ketone prepared title compound, and yield 86% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.00(d，1H)，8.50(d，1H)，8.33(d，1H)；7.87(d，1H)，7.75(d，1H)，7.63(dd，1H)，4.81(s，2H)，4.49(t，2H)，4.05(t，2H)，2.33(s，3H)。LCMS (method A): [MH] +=424, t R=4.54min.
Embodiment 45
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
6-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl)-7-fluoro-quinoline (45.1)
Use with the operation identical operations described in embodiment 40.2 synthetic and prepared title compound. 1H-NMR(400MHz，MeOH-d 4)δppm?8.85(d，1H)，8.33(d，1H)，8.26(d，1H)，7.96(d，1H)，7.72(d，1H)，7.51(dd，1H)，7.43(d，1H)，4.79(s，2H)。LCMS (method A): [MH] +=314, t R=4.61min.
6-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-ylmethyl]-7-fluoro-quinoline (45.2)
Use with the operation identical operations described in embodiment 40.3 synthetic and prepared title compound.LCMS (method B): [MH] +=350, t R=2.40min.
1-[3-(7-fluoro-quinoline-6-ylmethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (45.3)
Use with the operation identical operations described in embodiment 40.4 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.90(dd，1H)，8.18(d，1H)，8.05-8.13(m，1H)，7.75-7.87(m，3H)，7.37(dd，1H)，4.89(s，2H)，2.72(s，3H)。LCMS (method A): [MH] +=322, t R=1.97min.
(E)-2-(1-(3-((7-fluorine quinoline-6-yl) methyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 45)
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound.
1H-NMR(400MHz，DMSO-d 6)δppm?9.87(s，1H)，8.89(dd，1H)，8.31-8.39(m，2H)，8.20(d，1H)，8.04(d，1H)，7.78(d，1H)，7.50(dd，1H)，6.80(s?br，1H)，4.75(s，2H)，2.21(s，3H)。LCMS (method A): [MH] +=379, t R=5.80min.
Embodiment 46 and 46*
(E)-2-(1-(3-(1-(quinoline-6-yl) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives
Figure BDA0000151397020000911
6-{1-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-yl]-ethyl }-quinoline (46.1)
Use with the operation identical operations described in embodiment 40.3 synthetic and prepared title compound.LCMS (method A): [MH] +=346, t R=5.18min.
1-[3-(1-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (46.2)
Use with the operation identical operations described in embodiment 40.4 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.89(dd，1H)，8.05-8.17(m，3H)，7.78-7.84(m，2H)，7.71(d，1H)，7.39(dd，1H)，5.05(q，1H)，2.62(s，3H)，2.11(d，3H)。LCMS (method A): [MH] +=318, t R=3.88min.
(E)-2-(1-(3-(1-(quinoline-6-yl) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 46 and 46*)
Use the title compound that has prepared the racemic mixture form with the operation identical operations described in embodiment 40 synthetic. 1H-NMR(400MHz，DMSO-d 6)δppm?9.83(s，1H)，8.83(dd，1H)，8.28-8.33(m，2H)，8.16(d，1H)，7.92-7.97(m，2H)，7.78(dd，1H)，7.49(dd，1H)，6.78(s?br，2H)，5.03(q，1H)，2.15(s，3H)，1.92(d，3H)。LCMS (method A): [MH] +=375, t R=3.99min.Chiral separation (method G) provides the compound embodiment 46 and the 46* of enantiomer-pure.
Embodiment 47
(E)-2-(1-(3-(2-(quinoline-6-yl) propane-2-yl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
2-methyl-2-quinoline-6-base-propionyl hydrazine (47.1)
Use with 40.1 synthetic described in the operation identical operations prepared title compound.LCMS (method A): [MH] +=230, t R=2.71min.
6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-1-methyl-ethyl]-quinoline (47.2)
Use with the operation identical operations described in embodiment 40.2 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.89(dd，1H)，8.03-8.17(m，3H)，7.86(s，1H)，7.83(d，1H)，7.41(dd，1H)，7.06(d，1H)，5.00(q，1H)，2.05(d，3H)。LCMS (method A): [MH] +=310, t R=3.93min.
1-[3-(1-methyl isophthalic acid-quinoline-6-base-ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (47.3)
Use with the operation identical operations described in embodiment 40.4 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.88(dd，1H)，8.05-8.15(m，2H)，8.00(d，1H)，7.79(d，1H)，7.62(d，1H)，7.59(dd，1H)，7.40(dd，1H)，2.22(s，3H)，2.18(s，6H)。LCMS (method A): [MH] +=332, t R=4.19min.
(E)-2-(1-(3-(2-(quinoline-6-yl) propane-2-yl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 47)
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound.
1H-NMR(400MHz，DMSO-d 6)δppm?9.70(s，1H)，8.84(dd，1H)，8.37(dd，1H)，8.23(d，1H)，8.16(d，1H)，7.97(d，1H)，7.88(d，1H)，7.47-7.52(m，1H)，6.76(s?br，2H)，2.03(s，6H)，1.75(s，3H)。LCMS (method A): [MH] +=389, t R=4.14min.
Embodiment 48
(E)-1-methyl-2-(1-(3-(2-(quinoline-6-yl) propane-2-yl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000931
Use with the operation identical operations described in embodiment 47 synthetic and prepared title compound 1H-NMR (400MHz, CDCl 3) δ ppm 8.87 (dd, 1H), 8.09 (dd, 1H), 8.00 (d, 1H), 7.97 (d, 1H), 7.77 (d, 1H), 7.69 (d, 1H), 7.56 (dd, 1H), 7.38 (dd, 1H), 5.47 (sbr, 1H), 3.25 (s, 3H), 2.13 (s, 6H), 1.96 (s, 3H).LCMS (method A): [MH] +=403, t R=4.17min.
Embodiment 49
(E)-2-(1-(3-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000932
2-(5,7-two fluoro-quinoline-6-yl)-methyl propionate (49.1)
To (solution of 1.2M in THF, 9.5mL 11.40mmol) drip (5,7-difluoro-quinoline-6-yl)-methyl acetate (2.12g, 9.50mmol) solution in THF (20mL) in the solution in dry THF (30mL) in-78 ℃ LDA.Behind the 30min, (0.9mL 14.25mmol), makes reaction mixture slowly be warming up to 0 ℃ to drip MeI.Behind the 1h, use saturated NaHCO 3Aqueous solution cancellation is reacted and is extracted with EtOAc.Organic layer is used brine wash, use anhydrous Na 2SO 4Drying is filtered, and concentrates, and with flash chromatography method purifying, obtains the 2.272g title compound, is light yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?8.93(d，1H)，8.39(dd，1H)，7.61(dd，1H)，7.41-7.46(m，1H)，4.29(q，1H)，3.73(s，3H)，1.62(d，3H)。LCMS (method A): [MH] +=252, t R=5.09min.
2-(5,7-two fluoro-quinoline-6-yl)-propionyl hydrazine (49.2)
Use with 40.1 synthetic described in the operation identical operations prepared title compound.
1H-NMR(400MHz，DMSO-d 6)δppm?9.06(s，1H)，8.97(dd，1H)，8.45(d，1H)，7.58-7.67(m，2H)，4.23(s?br，2H)，4.08(q，1H)，1.51(d，3H)。LCMS (method A): [MH] +=252, t R=3.82min.
6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-ethyl]-5,7-two fluoro-quinoline (49.3)
Use with the operation identical operations described in embodiment 40.2 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.93(dd，1H)，8.36(dd，1H)，8.07(d，1H)，7.62(dd，1H)，7.43(dd，1H)，7.05(d，1H)，5.26(q，1H)，2，13(d，1H)。LCMS (method A): [MH] +=346, t R=5.00min.
6-{1-[6-(1-oxyethyl group-vinyl)-[1,2,4] triazolo [4,3-b] pyridazine-3-yl]-ethyl }-5,7-two fluoro-quinoline (49.4)
Use with the operation identical operations described in embodiment 40.3 synthetic and prepared title compound.LCMS (method A): [MH] +=382, t R=5.05min.
1-{3-[1-(5,7-two fluoro-quinoline-6-yl)-ethyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-yl }-ethyl ketone (49.5)
Use with the operation identical operations described in embodiment 40.4 synthetic and prepared title compound. 1H-NMR(400MHz，CDCl 3)δppm?8.92(dd，1H)，8.32(d，1H)，8.14(d，1H)，7.68(d，1H)，7.61(d，1H)，7.42(dd，1H)，5.32(q，1H)，2.43(s，3H)，2.21(d，3H)。LCMS (method A): [MH] +=354, t R=4.42min.
(E)-2-(1-(3-(1-(5,7-difluoro-quinoline-6-yl) ethyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 49)
Use with the operation identical operations described in embodiment 40 synthetic and prepared title compound. 1H-NMR(400MHz，DMSO-d 6)δppm?9.76(s，1H)，8.96(d，1H)，8.44(d，1H)，8.29(d，1H)，8.17(d，1H)，7.70(d，1H)，7.59(dd，1H)，6.77(s?br，2H)，5.24(q，1H)，2.01(d，3H)，1.87(s，3H)。LCMS (method A): [MH] +=411, t R=4.28min.
Embodiment 50
(E)-1-methyl-2-(1-(3-(1-(quinoline-6-yl) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000951
1-quinoline-6-base-cyclopropane-carboxylic acid methyl esters (50.1)
Under nitrogen atmosphere, in-78 ℃, ((2.14g is 10.64mmol) in the solution in dry THF (40mL) 26.6mmol) to be added drop-wise to quinoline-6-base-methyl acetate for the solution of 1.8M in toluene, 14.8ml with LDA solution.Behind the 30min, go through 3min drip glycol dibromide (2.40g, 12.76mmol).The mixture of gained in stirring at room 1h, is used saturated NH then 4The cancellation of the Cl aqueous solution.Mixture is extracted with DCM, use brine wash, use Na 2SO 4Dry also removing desolvated.Resistates with silica gel flash chromatography method purifying, with EtOAC/ hexane gradient wash-out, is obtained 463mg (20%) title compound, be yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?8.91(dd，1H)，8.12(d，1H)，8.07(d，1H)，7.77-7.74(m，2H)，7.40(dd，1H)，3.65(s，3H)，1.73-1.71(m，2H)，1.33-1.30(m，2H)。LCMS (method A): [MH] +=228, t R=4.37min.
1-quinoline-6-base-Trimetylene formyl hydrazine (50.2)
(513mg is 2.26mmol) with single Hydrazine Hydrate 80 (3.39g, 67.7mmol) heated overnight under refluxing of the solution in methyl alcohol (5mL) with 1-quinoline-6-base-cyclopropane-carboxylic acid methyl esters.After the cooling, solvent removed in vacuo obtains 513mg (100%) title compound, and it is used without being further purified promptly.LCMS (method A): [MH] +=228, t R=2.88min.6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-cyclopropyl]-quinoline (50.3)
In microwave tube, pack into 1-quinoline-6-base-Trimetylene formyl hydrazine (513mg, 2.26mmol), 3, the 6-dichloro-pyridazine (437mg, 2.93mmol) and propyl carbinol (5mL).Mixture is heated 12h in 140 ℃.Solvent removed in vacuo with silica gel flash chromatography method purifying, with ETOAC/ methyl alcohol gradient elution, obtains 196mg (41%) title compound with resistates.LCMS (method A): [MH] +=322, t R=4.38min.
1-[3-(1-quinoline-6-base-cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (50.4)
With 6-[1-(6-chloro-[1,2,4] triazolo [4,3-b] pyridazine-3-yl)-cyclopropyl]-quinoline (30mg, 0.093mmol), PdCl 2(PPh 3) 2(6.5mg, 0.0093mmol) and tributyl (1-vinyl ethyl ether base) stannane (67mg, 0.186mmol) 1,4-two
Figure BDA0000151397020000961
Solution in the alkane (3mL) is at N 2Down in 90 ℃ of heating 3h.Reaction mixture is diluted with EtOAc, use the KF solution washing.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration.Be dissolved among HOAc and the 3NHCl resistates and in stirring at room 3h.Solvent removed in vacuo is dissolved in resistates among the DCM, uses saturated NaHCO 3The aqueous solution and brine wash.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration.Resistates with silica gel flash chromatography method purifying, is used the EtOAC/MeOH gradient elution, obtain title compound, be yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?8.89(dd，1H)；8.13-8.04(m，3H)，7.93(d，1H)，7.87(dd，1H)，7.70(d，1H)，7.40(dd，1H)，2.51(s，3H)，1.92-1.89(m，2H)，1.73-1.69(m，2H)。LCMS (method A): [MH] +=330, t R=4.18min.
(E)-1-methyl-2-(1-(3-(1-(quinoline-6-yl) cyclopropyl)-[1,2,4] triazolo [4,3-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 50)
With 1-[3-(1-quinoline-6-base-cyclopropyl)-[1; 2,4] triazolo [4,3-b] pyridazine-6-yl]-ethyl ketone (30mg; 0.091mmol), (16.2mg, 0.18mmol) solution in methyl alcohol (5mL) is in stirred overnight at room temperature for acetate (0.1mL) and 1-methyl hydrazine methane amide.Solvent removed in vacuo is diluted resistates with DCM, use saturated NaHCO 3Solution washing.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration.Resistates with silica gel flash chromatography method purifying, is used CH 2Cl 2/ MeOH gradient elution obtains title compound (14.9mg, 41%), is yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?8.84(dd，1H)，8.30(d，1H)，8.22(d，1H)，8.13(d，1H)，7.94-7.92(m，2H)，7.70(dd，1H)，7.49(dd，1H)，6.64(s，2H)，3.21(s，3H)，2.16(s，3H)，1.78-1.75(m，2H)，1.68-1.65(m，2H)。LCMS (method A): [MH] +=401, t R=4.11min.
Embodiment 51
(E)-2-(1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000971
6-((6-bromine imidazo [1,2-a] pyrimidin-3-yl) methyl) quinoline (51.1)
(1.0g, 2.54mmol) (0.53g, 3.05mmol) solution in 2-methyl-T-2-alcohol (10mL) stirs 12h in 135 ℃ with 5-bromo pyrimi piperidine-2-amine with 2-chloro-3-(quinoline-6-yl) propionic aldehyde.After the cooling, solvent removed in vacuo with silica gel flash chromatography method purifying, is used CH with resistates 2Cl 2/ MeOH gradient elution obtains the mixture (250mg, 29%) of title compound and 6-(6-bromo-imidazo [1,2-a] pyrimidine-2-base methyl) quinoline, is brown solid.LCMS (method E): [MH] +=339/341, t R=3.51min.
1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-yl) ethyl ketone (51.2)
With 6-((6-bromine imidazo [1,2-a] pyrimidin-3-yl) methyl) quinoline and 6-(6-bromo-imidazo [1,2-a] pyrimidine-2-base methyl) quinoline (mixture, 250mg, 0.737mmol), PdCl 2(PPh 3) 2(51.7mg, 0.074mmol) and tributyl (1-vinyl ethyl ether base) stannane (399mg, 1.106mmol) at 5mL1,4-two Solution in the alkane is at N 2Down in 80 ℃ of heating 12h.Reaction mixture is diluted with EtOAc, use water washing.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration. resistates is dissolved among HOAc and the 3NHCl and in stirring at room 3 hours.Under reduced pressure remove and desolvate, resistates is dissolved in CH 2Cl 2In, use saturated NaHCO 3The aqueous solution and brine wash.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration.Resistates with silica gel flash chromatography method purifying, is used the EtOAc/MeOH gradient elution, obtain title compound, be yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?8.97(d，1H)，8.84(d，1H)，8.67(d，1H)，8.04-7.99(m，2H)，7.74(s，1H)，7.53-7.51(m，1H)，7.34(dd，1H)，7.19(s，1H)，4.44(s，2H)，2.49(s，3H)。
(E)-2-(1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-yl) ethidine)-Hydrazinecarboxamidederivatives (embodiment 51)
(40mg, 0.132mmol) (14.9mg, 0.198mmol) solution in methyl alcohol (3mL) stirs 2h in 40 ℃ with the Hydrazinecarboxamidederivatives hydrochloride with 1-(3-(quinoline-6-ylmethyl) imidazo [1,2-a] pyrimidine-6-yl) ethyl ketone.Solvent removed in vacuo is used the HPLC purifying with resistates, obtains 4.2mg (8.8%) title compound, is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.45(s，1H)，9.24(d，1H)，8.91(d，1H)，8.86(dd，1H)，8.30(d，1H)，7.98(d，1H)，7.89(s，1H)，7.72(dd，1H)，7.52-7.49(m，2H)，6.65(s，2H)，4.59(s，2H)，2.18(s，3H)。LCMS (method A): [MH] +=360, t R=2.95min.
Embodiment 52
(E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020000981
6-bromo-N2-(quinoline-6-ylmethyl) pyrazine-2,3-diamines (52.1)
With quinoline-6-base methylamine (3.6g, 22.76mmol), 3,5-two bromo-pyrazines-2-amine (5.75g, 22.76mmol) and triethylamine (4.61g, mixture 45.5mmol) are heated to 130 ℃ and reach 5h in microwave.Reaction mixture is used CH 2Cl 2With the water dilution, separate organic layer, use NH 4The Cl solution washing is used Na 2SO 4Drying is filtered and vacuum concentration.(EA: purifying hexane) obtains 6-bromo-N2-(quinoline-6-ylmethyl) pyrazine-2,3-diamines (6.93g, 92%) with silica gel chromatography with resistates.LCMS (method A): [MH] +=330, t R=4.89min.
6-((6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline (52.2)
To 6-bromo-N2-(quinoline-6-ylmethyl) pyrazine-2, (6.55g 19.84mmol) adds Sodium Nitrite (2.74g, 39.7mmol) solution in water (3mL) to the 3-diamines in the solution in acetate (15mL).Behind stirring at room 3h, with solution for vacuum concentration.Resistates is used NaHCO 3(aqueous solution) absorbs, and extracts with DCM.Organic layer is used NH 4Na is used in Cl (aqueous solution) washing 2SO 4Drying is filtered, and also (EA: purifying hexane) obtains 6-((6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline (3.35g, 47%) to vacuum concentration with silica gel chromatography. 1H-NMR(400MHz，DMSO-d 6)δppm?9.05(s，1H)，8.89(d，1H)，8.34(d，1H)，8.02(d，1H)，7.93(s，1H)，7.76(dd，1H)，7.53(dd，1H)，6.19(s，2H)。LCMS (method B): [MH] +=343, t R=2.11min.
6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline (52.3)
(2.50g 5.86mmol) adds Pd (Ph in the solution in DMF (20mL) to quinoline to the 6-((6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) of the degassing 3P) 4(0.542g, 0.469mmol), with solution in stirring at room 20min.Add then tributyl (1-vinyl ethyl ether base) stannane (2.117g, 5.86mmol).Reaction is heated to 100 ℃, shows until LC-MS to react completely.Reaction mixture is filtered through celite,, use Na the filtrate water washing 2SO 4Dry and concentrated.The crude product of gained with silica gel column chromatography (gradient Hex:EA) purifying, is obtained 6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline (1.2g, 62%). 1H-NMR(400MHz，CDCl 3)δppm?9.19(s，1H)，8.94(m，1H)，8.20(m，1H)，7.99(s，1H)，7.89(d，1H)，7.548(m，1H)，6.12(s，2H)，5.61(d，1H)，4.61(d，1H)，4.05(q，2H)，1.51(t，3H)。LCMS (method B): [MH] +=360, t R=2.40min.1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone (52.4)
(150mg 0.451mmol) adds 3N HCl (0.1mL) in the solution in acetate to 6-((6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline.Solution behind stirring at room 2h, is under reduced pressure removed and desolvates.The dilute with water resistates is also used NaHCO 3The aqueous solution transfers to alkalescence with its pH, extracts with DCM.The organic layer that merges is used NaHCO 3(aqueous solution) and brine wash are used Na 2SO 4Drying is filtered and vacuum concentration.Resistates is used the silica gel column chromatography purifying, obtain 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone yellow solid (131mg, 91%). 1H-NMR(400MHz，CDCl 3)δppm?9.45(s，1H)，8.95(d，1H)，8.14(m，2H)，7.95(s，1H)，7.84(d，1H)，7.45(m，1H)，6.19(s，2H)，2.75(s，3H)。LCMS (method B): [MH] +=305, t R=2.95min.
(E)-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 52)
To 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone (35mg, 0.115mmol) add in the solution in MeOH (3mL) the Hydrazinecarboxamidederivatives hydrochloride (115mg, 1.035mmol).Solution is heated to 37 ℃ to spend the night.Add triethylamine (1mL), with solution in stirring at room 20min.Solvent removed in vacuo is diluted resistates with DCM, use brine wash, uses Na 2SO 4Drying is filtered and vacuum concentration, obtains the 25mg title compound, and yield 57% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.90(s，1H)，9.85(s，1H)，8.89(m，1H)，3.36(d，1H)，8.01(m，2H)，7.82(d，1H)，7.53(dd，1H)，6.17(s，2H)，2.32(s，3H)。LCMS (method A): [MH] +=384, t R=4.09min.
Embodiment 53
(E)-2-morpholino-N '-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) acethydrazide
Figure BDA0000151397020001001
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and 2-morpholino acethydrazide.Obtained title compound with the faint yellow solid form. 1H-NMR(400MHz，DMSO-d 6)δppm?9.45(d，1H)，8.90(d，1H)，8.36(d，1H)，8.01(m，2H)，7.83(d，1H)，7.53(dd，1H)，6.20(s，2H)，3.65(d，4H)，3.26(s，2H)，2.57(d，4H)，2.41(s，3H)。LCMS (method B): [MH] +=446.2, t R=1.37min.
Embodiment 54
(E)-2-(4-N-METHYL PIPERAZINE-1-yl)-N '-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) acethydrazide
Figure BDA0000151397020001011
Be similar to the synthetic of embodiment 52 and prepared title compound, be faint yellow solid by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl).LCMS (method B): [MH] +=459, t R=1.35min.
Embodiment 55
(E)-3-(1-(1-(quinoline-6-ylmethyl)-1H-[1; 2; 3] triazolo [4,5-b] pyrazine-6-yl) ethidine is amino) azoles alkane-2-ketone
Figure BDA0000151397020001013
Be similar to the synthetic of embodiment 52 by 1-(1-(quinoline-6-ylmethyl)-1H-[1; 2; 3] triazolo [4,5-b] pyrazine-6-yl) amino azoles alkane-2-ketone of ethyl ketone and 3-has prepared title compound. 1H-NMR(400MHz，DMSO-d 6)δppm?9.42(s，1H)，8.89(m，1H)，8.36(d，1H)，8.02(m，2H)，7.84(m，1H)，7.53(m，1H)，6.24(s，2H)，4.51(t，2H)，4.15(t，1H)，4.08(t，2H)，2.73(s，1H)，2.46(s，3H)。LCMS (method B): [MH] +=389, t R=1.87min.
Embodiment 56
(E)-and 1-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine is amino)-imidazolidine-2, the 4-diketone
Figure BDA0000151397020001015
Be similar to synthesizing by 1-aminooimidazole alkane-2 of embodiment 52,4-dione hydrochloride and 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone has prepared title compound, and yield 58% is faint yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?11.45(s，1H)，9.41(s，1H)，8.89(d，1H)，8.35(d，1H)，8.02(m，2H)，7.84(d，1H)，7.53(dd，1H)，6.23(s，2H)，4.56(s，2H)，2.49(s，3H)。LCMS (method B): [MH] +=402, t R=1.81min.
Embodiment 57
(E)-1-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine is amino)-imidazolidin-2-one
Figure BDA0000151397020001021
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and 1-aminooimidazole alkane-2-ketone, yield 26% is faint yellow solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.42(s，1H)，8.89(d，1H)，8.35(d，1H)，8.02(m，2H)，7.84(d，1H)，7.53(dd，1H)，7.36(s，1H)，6.22(s，2H)，3.75(t，2H)，3.41(t，2H)，2.42(s，3H)。LCMS (method B): [MH] +=388, t R=1.89min.
Embodiment 58
(E)-N '-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine)-methylsulfonyl hydrazine
Figure BDA0000151397020001022
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and methylsulfonyl hydrazine. 1H-NMR(400MHz，DMSO-d 6)δppm?9.45(s，1H)，8.89(m，1H)，8.36(d，1H)，7.82(m，2H)，7.85(dd，1H)，7.53(dd，1H)，6.21(s，2H)，3.20(s，3H)，2.35(s，3H))。LCMS (method B): [MH] +=446, t R=1.37min.
Embodiment 59
[1-(3-quinoline-6-ylmethyl-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl)-second-(E)-the fork base]-hydrazine
Figure BDA0000151397020001031
Be similar to the synthetic of embodiment 52 and prepared title compound, yield 36% by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?9.50，9.3(s，1H)，8.89(m，1H)，8.35(d，1H)，7.99(m，2H)，7.80(d，1H)，7.72(s，1H)，7.53(dd，1H)，6.22，6.12(s，2H)，2.28，2.14(s，3H)。
Embodiment 60
(E)-1-methyl-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001032
Be similar to the synthetic of embodiment 52 and prepared title compound, be white solid by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and 1-methyl hydrazine-methane amide. 1H-NMR(400MHz，DMSO-d 6)δppm?9.68(s，1H)，8.89(m，1H)，8.36(d，1H)，8.03(s，1H)，8.01(d，1H)，7.82(dd，1H)，7.53(dd，1H)，6.75(s，2H)，6.21(s，2H)2.50(s，3H)，2.49(s，3H)。LCMS (method B): [MH] +=376, t R=1.88min.
Embodiment 61
(E)-N-methyl-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and N-methyl hydrazine-methane amide. 1H-NMR(400MHz，DMSO-d 6)δppm?10.04(s，1H)，9.88(s，1H)，8.89(m，1H)，8.36(d，1H)，8.02(m，2H)，7.82(d，1H)，7.52(dd，1H)，7.45(m，1H)，6.17(s，2H)，2.74(d，3H)，2.31(s，3H)。LCMS (method B): [MH] +=376, t R=2.95min.
Embodiment 62
(E)-and N, 1-dimethyl--2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001041
Be similar to the synthetic by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and N of embodiment 52,1-dimethyl--Hydrazinecarboxamidederivatives has prepared title compound. 1H-NMR(400MHz，DMSO-d 6)δppm?9.73(s，1H)，8.89(m，1H)，8.36(dd，1H)，8.03(s，1H)，8.00(d，1H)，7.53(dd，1H)，7.19(m，1H)，6.21(s，2H)，3.31(s，3H)，2.72(d，3H)，2.49(d，3H)。LCMS (method B): [MH] +=390, t R=1.99min.
Embodiment 63
(E)-1-ethyl-2-(1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone and 1-ethyl hydrazine-methane amide, yield 57% is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.61(s，1H)，8.89(d，1H)，8.36(d，1H)，8.03(s，1H)，8.00(d，1H)，7.83(d，1H)，7.53(m，1H)，6.61(d，2H)，6.22(s，2H)，3.80(q，2H)，2.42(s，3H)，1.07(t，3H)。LCMS (method B): [MH] +=390, t R=1.98min.
Embodiment 64
(E)-N '-ethanoyl-1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-hydrazine is for carbonyl acid amides (carbohydrazonamide)
Figure BDA0000151397020001051
1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formonitrile HCN (64.1)
(1.6g 4.69mmol) adds Pd (PPh in the solution in DMF (8mL) to quinoline to the 6-((6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) of the degassing 3) 4(0.434g, 0.375mmol) with dicyano zinc (dicyanozinc) (0.441g, 3.75mmol).Reaction mixture is heated to 127 ℃ reaches 4h.Add NH 4Cl (aqueous solution) adds EtOAc then with the cancellation reaction.Reaction mixture is filtered through celite, use saturated NaHCO 3And NH 4The Cl washing.Separate organic layer, use Na 2SO 4Drying is filtered also and is concentrated, and obtains crude product, with its with Analogix silica gel (hexane: EtOAc) purifying, obtain title compound, be faint yellow solid.LCMS (method B): [MH] +=288, t R=1.81min.
1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-hydrazine is for carbonyl acid amides (64.2)
To 1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formonitrile HCN (80mg, 0.278mmol) add in the solution in EtOH (3mL) Hydrazine Hydrate 80 (18.12mg, 0.362mmol).Reaction is heated to 60 ℃ spends the night.Filtering mixt is with EtOH, H 2O and EtOH washing obtain yellow solid. 1H-NMR(400MHz，DMSO-d 6+D 2O)δppm?9.29(s，1H)，8.88(s，1H)，8.34(d，1H)，8.01(m，2H)，7.83(d，1H)，7.52(m，1H)，6.16(s，2H)。LCMS (method B): [MH] +=320, t R=1.03min.
((E)-N '-ethanoyl-1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-hydrazine is for carbonyl acid amides (embodiment 64)
To 1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4; 5-b] pyrazine-6-hydrazine is for carbonyl acid amides (25mg; 0.078mmol) add in the solution in DMSO (1mL) and DCM (2.0mL) pyridine (6.19mg, 0.078mmol) and diacetyl oxide (10.39mg, 0.102mmol).After the stirred overnight, filter reaction mixture.With solid with EtOH, H 2O and EtOH washing obtain the 19.9mg title compound, yield 67%. 1H-NMR(400MHz，DMSO-d 6)δppm?9.48(d，1H)，8.88(d，1H)，8.34(d，1H)，8.05(s，1H)，8.01(d，1H)，7.86(d，1H)，7.53(dd，1H)，6.20(s，2H)，2.24(s，1H)，2.00(s，1H)。LCMS (method B): [MH] +=362, t R=1.60min.
Embodiment 65
(E)-2-(amino (1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) methene base) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001061
Be similar to the synthetic of compound 64.2 and prepared title compound by 1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formonitrile HCN and Hydrazinecarboxamidederivatives hydrochloride. 1H-NMR(400MHz，DMSO-d 6)δppm?9.80(s，1H)，8.88(m，1H)，8.34(d，1H)，8.05(d，1H)，8.00(d，1H)，7.86(d，1H)，7.52(dd，1H)，6.18(s，2H)。LCMS (method B): [MH] +=363, t R=1.70min.
Embodiment 66
(E)-2-((1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) methene base)-Hydrazinecarboxamidederivatives
6-((6-vinyl-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline (66.1)
(1200mg 3.52mmol) adds Pd (PPh in the solution in DMF (10mL) to quinoline to the 6-((6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) of the degassing 3) 4(610mg, 0.528mmol).With solution stirring 20min, add then tributyl (vinyl) stannane (1227mg, 3.87mmol).Reaction mixture is heated to 120 ℃ reaches 5h.Add NH 4Cl (aqueous solution) adds EtOAc then with the cancellation reaction.Through the celite filter reaction mixture, will filtrate and use saturated NaHCO 3, saturated NH 4The Cl washing.Separate organic layer, use Na 2SO 4Dry and concentrated, obtain crude product, (hexane: EA) purifying obtains the 210mg title compound, yield 20% with Analogix silica gel with it.LCMS (method B): [MH] +=288, t R=2.05min.
1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-formaldehyde (66.2)
(100mg, 0.347mmol) with 2, (74.3mg, (297mg is 1.387mmol) at H to add osmium oxide (VIII) in mixture 0.694mmol) for the 6-lutidine to 6-((6-vinyl-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) methyl) quinoline 2Solution among the O (1.333mL), 1,4-two to add sodium periodate (88mg, 6.94 μ mol) then
Figure BDA0000151397020001071
Solution in the alkane (4ml).With reaction mixture in stirring at room 10h.Solvent removed in vacuo adds DCM dilution resistates.The solution of gained is used saturated NaHCO 3, NH 4Cl and brine wash.Separate organic layer, use Na 2SO 4Dry and concentrated, obtain crude product, (hexane: EA) purifying obtains the 45mg title compound, yield 43% with Analogix silica gel with it.LCMS (method B): [MH] +=291, t R=1.00min.
(E)-2-((1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) methene base) Hydrazinecarboxamidederivatives (embodiment 66)
Be similar to compound 52 synthetic by 1-(quinoline-6-ylmethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-prepared formaldehyde title compound, yield 65%. 1H-NMR(400MHz，DMSO-d 6)δppm?9.68(s，1H)，8.88(m，1H)，8.33(m，1H)，7.99(m，2H)，7.91(s，1H)，7.76(m，1H)，7.52(dd，1H)，6.16(s，2H)。LCMS (method B): [MH] +=348, t R=1.60min.
Embodiment 67
(E)-2-(1-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001081
6-bromo-N2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2,3-diamines (67.1)
Be similar to the synthetic of compound 52.1 and prepared title compound, be white solid by 1-(7-fluorine quinoline-6-yl) ethamine.LCMS (method B): [MH] +=364, t R=2.38min.
6-(1-(6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline (67.1)
Be similar to the synthetic by 6-bromo-N2-(1-(7-fluorine quinoline-6-yl) ethyl) pyrazine-2 of compound 52.2, the 3-diamines has prepared title compound.LCMS (method B): [MH] +=345, t R=2.36min.
6-(1-(6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline (67.3)
Be similar to the synthetic of compound 52.3 and prepared title compound by 6-(1-(6-bromo-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline. 1H-NMR(400MHz，CDCl 3)δppm9.17(9.17(s，1H)，8.90(m，1H)，8.10(d，1H)，7.89(d，1H)，7.78(d，1H)，7.39(dd，1H)，6.82(q，1H)，5.56(d，1H)，4.56(d，1H)，4.04(q，2H)，2.30(d，3H)，1.48(t，3H)。LCMS (method B): [MH] +=365, t R=2.55min.
1-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone (67.4)
Be similar to the synthetic of compound 52.4 and prepared title compound by 6-(1-(6-(1-vinyl ethyl ether base)-1H-[1,2,3] triazolo [4,5-b] pyrazine-1-yl) ethyl)-7-fluorine quinoline. 1H-NMR(400MHz，CDCl 3)δppm?9.44(s，1H)，8.93(m，1H)，8.13(d，1H)，7.94(s，1H)7.79(d，1H)，7.41(dd，1H)，6.88(q，1H)，2.76(s，3H)，2.37(d，3H)。LCMS (method B): [MH] +=337, t R=2.21min.
(E)-2-(1-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 67)
Be similar to the synthetic of embodiment 52 and prepared title compound by 1-(1-(1-(7-fluorine quinoline-6-yl) ethyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δ?ppm?9.69(s，1H)，8.89(d，1H)，8.43(d，1H)，8.22(d，1H)，7.73(d，1H)，7.55(dd，1H)，8.86(q，1H)，2.34(d，3H)，2.31(s，3H)。LCMS (method B): [MH] +=394, t R=2.13 min.
Embodiment 68
(E)-2-(1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001091
1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl)-1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethanol (68.1)
To (1.800 g 7.86mmol) drip n-BuLi (5.40 ml, 8.64 mmol) in the solution in THF (79 ml) in-100 ℃ 5-bromo-6-fluoro-1-methyl isophthalic acid H-indazole.In-100 ℃ stir 1h after, drip 1-(6-chlorine imidazo [1,2-b] pyridazine-3-yl) ethyl ketone in THF (20mL) (1.691g, 8.64mmol).Reaction soln is stirred other 2h and uses NH 4Cl (aqueous solution) cancellation.Mixture with EtOAc extraction gained.The organic layer that merges is used NH 4Na is used in Cl (aqueous solution) washing 2SO 4Dry also vacuum concentration obtains crude product, and (hexane: EtOAc) purifying obtains title compound, yield 34% with silica gel column chromatography with it.LCMS (method B): [MH] +=346, t R=2.14 min.
6-chloro-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine (68.2)
With 1-(6-chlorine imidazo [1; 2-b] pyridazine-3-yl)-1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethanol (1.1 g; 3.18 mmol), the crystalline flake of iodine (diiodine) (2.019 g; 7.95 mmol) and the mixture heating up to 120 of phospho acid (0.840 g, 12.73 mmol) in HOAc (10 ml) ℃ reach 5h.After being cooled to room temperature, with the reaction mixture vacuum concentration.Water absorption of residual excess transfers to 8 with the NaOH aqueous solution with its pH.Extract mixture with DCM, use Na 2SO 4Dry and concentrated, obtain resistates, it with silica gel column chromatography (MeOH:EA) purifying, is obtained 6-chloro-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine (900mg 60%).LCMS (method B): [MH] +=330, t R=2.59min.
6-(1-vinyl ethyl ether base)-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine (68.3)
(900mg 1.910mmol) adds Pd (Ph in the solution in DMF (8mL) to imidazo [1,2-b] pyridazine to 6-chloro-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) 3P) 4(221mg, 0.191mmol).Mixture is stirred 20min, and adding tributyl (1-vinyl ethyl ether base) stannane (784mg, 2.102mmol).With the mixture heating up to 100 of gained ℃, show until LC-MS to react completely.Through the celite filter reaction mixture, use the ether wash solids.With the filtrate water washing, use Na then 2SO 4Dry and concentrated, obtain resistates, it with silica gel column chromatography (gradient Hex:EA) purifying, is obtained 6-(1-vinyl ethyl ether base)-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine (450mg, 52%).
1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (68.4)
(450mg 0.985mmol) adds 3N HCl (0.5mL) in the solution in acetate (8mL) to 6-(1-vinyl ethyl ether base)-3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl)-imidazo [1,2-b] pyridazine.Solution in stirring at room 2h, is under reduced pressure removed and desolvates.The dilute with water resistates is also used NaHCO 3The aqueous solution transfers to alkalescence with its pH, extracts with DCM.Organic layer is used NaHCO 3(aqueous solution) and brine wash are used Na 2SO 4Dry also vacuum concentration.Resistates is used the silica gel column chromatography purifying, obtain yellow solid 1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (300mg, 81%).LCMS (method B): [MH] +=338, t R=2.49min.
(E)-2-(1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 68)
To 1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (35mg, 0.104mmol) add in the solution in MeOH (4mL) the Hydrazinecarboxamidederivatives hydrochloride (28.9mg, 0.259mmol).Reaction mixture is heated to 35 ℃.After stirring 5h, remove and desolvate, add DCM dilution resistates.Then the mixture of gained is used brine wash, use Na 2SO 4Dry also vacuum concentration obtains (E)-2-(1-(3-(1-(6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (14mg, 33%), is white solid. 1H-NMR(400MHz，DMSO-d 6)δppm?9.64(s，1H)，8.14(d，1H)，7.93(m，2H)，7.74(s，1H)，7.51(m，2H)，4.93(m，1H)，3.96(s，3H)，2.13(s，3H)，1.76(d，3H)。LCMS (method B): [MH] +=395, t R=2.32min.
Embodiment 69
(E)-2-(1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001111
6-chlorine imidazo [1,2-b] pyridazine-3-yl) (6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl alcohol (69.1)
Be similar to the title compound that synthesized by 6-chlorine imidazo [1,2-b] pyridazine-3-prepared formaldehyde of compound 68.1, be yellow solid.LCMS (method B): [MH] +=332, t R=2.09min.6-chloro-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine (69.2)
Be similar to the synthetic of compound 68.2 and prepared title compound, be yellow solid by (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl alcohol.LCMS (method B): [MH] +=316, t R=2.56min.
6-(1-vinyl ethyl ether base)-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine (67.3)
Be similar to the synthetic of compound 68.3 and prepared title compound by 6-chloro-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine.
1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (67.4)
Be similar to the synthetic of compound 68.4 and prepared title compound, be white solid by 6-(1-vinyl ethyl ether base)-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine.LCMS (method B): [MH] +=324, t R=2.41min.
(E)-2-(1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 67)
Be similar to the synthetic of embodiment 68 and prepared title compound, be white solid by 1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?9.71(s，1H)，8.19(s，1H)，7.96(m，2H)，7.69(d，1H)，7.55(s，1H)，7.54(d，1H)，4.41(s，2H)，3.97(s，3H)，2.28(s，3H)。LCMS (method B): [MH] +=381, t R=2.20min.
Embodiment 70
(E)-2-(1-(3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001121
(6-chlorine imidazo [1,2-b] pyridazine-3-yl) (1-methyl isophthalic acid H-indazole-5-yl) methyl alcohol (70.1)
In-10 ℃, to 3-bromo-6-chlorine imidazo [1,2-b] pyridazine (232.0mg, 1.00mmol) add in the solution in 5mLTHF ethyl-magnesium-bromide (1.50mL, 1.50mmol).In-10 ℃ stir 1 hour after, add 1-methyl isophthalic acid H-indazole-5-formaldehyde (240.0mg, 1.50mmol).Make mixture slowly be warmed to room temperature and stirred other 2 hours.Use saturated NH 4Cl solution cancellation reaction also under reduced pressure concentrates.The dilute with water resistates is also used the EtOAc extracted twice.Merge organic layer, use Na 2SO 4Dry and concentrated.Crude product is washed with DCM, obtain title compound, be white solid (230mg, 70%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.21(d，1H)，8.02(s，1H)，7.81(s，1H)，7.59(d，1H)，7.56(s，1H)，7.49(d，1H)，7.35(d，1H)，6.29(d，1H)，6.21(d，1H)，4.02(s，3H)。LCMS (method A): [MH] +=314, t R=4.44min6-chloro-3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine (70.2):
With (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (1-methyl isophthalic acid H-indazole-5-yl) methyl alcohol (156.8mg, 0.50mmol), I 2(381mg, 1.50mmol) and H 3PO 2(0.273mL, 2.50mmol) solution in 4mL AcOH was in 110 ℃ of heating 7 hours.Under reduced pressure remove and desolvate.The dilute with water resistates is also used the DCM extracted twice.Merge organic layer, use Na 2SO 4Dry and concentrated.With crude product with the flash chromatography method (DCM: MeOH=20: 1) purifying, obtain title compound, it contains some iodine, and it promptly is used for next step (180.0mg, 44%, 36% purity) without being further purified.LCMS (method A): [MH] +=298, t R=5.37min
6-(1-oxyethyl group-vinyl)-3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine (70.3):
With 6-chloro-3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine (180.0mg, 36% purity, 0.22mmol), tributyl (1-vinyl ethyl ether base) stannane (94mg, 0.26mmol) and Pd (PPh 3) 4(25.1mg, 0.02mmol) suspension in 10mL DMF is used nitrogen wash, then in 110 ℃ of heating and stirred overnight.Under reduced pressure remove and desolvate, resistates is diluted with DCM, use KF solution and water washing successively.Organic layer is used Na 2SO 4Drying is filtered and vacuum concentration.With crude product with the flash chromatography method (DCM: MeOH=20: 1) purifying, obtain title compound, it contains some triphenyl phosphine oxide impurity, and it promptly is used for next step (49mg, 47%, 70% purity) without being further purified.LCMS (method A): [MH] +=334, t R=5.71min.
1-(3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (70.4):
With 6-(1-oxyethyl group-vinyl)-3-(1-methyl isophthalic acid H-indazole-5-ylmethyl)-imidazo [1,2-b] pyridazine (50mg, 0.15mmol) and HCl (0.15mL, 0.15mmol) solution in 10mL AcOH in 50 ℃ the heating 3 hours.Under reduced pressure remove and desolvate.The dilute with water resistates is used NaHCO 3The aqueous solution transfers to the pH value of solution about 8, with DCM extraction three times.Merge organic layer, use Na 2SO 4Dry and concentrated.With not purified promptly be used for next step (45mg, 75%, 76% purity) of crude product.LCMS (method A): [MH] +=306, t R=5.03min.
(E)-2-(1-(3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 70):
With 1-(3-((1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (40.0mg, 0.09mmol) and Hydrazinecarboxamidederivatives (19.47mg, 0.26mmol) solution in 10mL THF is in 40 ℃ of stirred overnight.Solvent removed in vacuo.With crude product with the flash chromatography method (DCM: MeOH=20: 1) purifying, obtain title compound, be white solid (29.0mg, 88%). 1H-NMR(400MHz，DMSO-d 6)δppm?9.71(s，1H)，8.18(d，1H)，7.95(m，2H)，7.69(s，1H)，7.60(s，1H)，7.75(d，1H)，7.40(dd，1H)，6.76(bs，2H)，4.41(s，2H)，3.99(s，3H)，2.29(s，3H)。LCMS (method A): [MH] +=363, t R=4.42min.
Embodiment 71
(E)-2-(1-(3-(1-(1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
(6-chlorine imidazo [1,2-b] pyridazine-3-yl) (1-methyl isophthalic acid H-indazole-5-yl) ketone (71.1):
With (6-chlorine imidazo [1; 2-b] pyridazine-3-yl) (1-methyl isophthalic acid H-indazole-5-yl) methyl alcohol (500.0mg; 1.60mmol) and 2-iodoxybenzene formic acid (2.39mmol) suspension in 10mL acetone heats under refluxing and stirred 3 hours for 45% purity, 1488.0mg.Under reduced pressure remove and desolvate.The dilute with water resistates transfers to about 10 with the pH value of the 10%NaOH aqueous solution with solution.Through filtering the collecting precipitation thing, with water washing three times.Solid is dissolved among the DCM, uses Na 2SO 4Drying is filtered and is concentrated, and obtains title compound, is white solid (410.0mg, 78%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.46(s，1H)，8.42(m，1H)，8.32(m，1H)，8.27(d，1H)，7.95(dd，1H)，7.815(d，1H)，7.66(d，1H)，4.12(s，2H)。LCMS (method A): [MH] +=312, t R=4.64min.
1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-1-(1-methyl isophthalic acid H-indazole-5-yl)-ethanol (71.2):
In 0 ℃, to (6-chlorine imidazo [1,2-b] pyridazine-3-yl) (1-methyl isophthalic acid H-indazole-5-yl) ketone (410mg, 1.32mmol) add in the solution in 10mL THF the iodate methyl magnesium (0.88mL, 2.63mmol).After 3 hours, use saturated NH in 0 ℃ of stirring 4Cl cancellation reaction under reduced pressure concentrates.
Resistates is extracted three times with DCM.Merge organic layer, use Na 2SO 4Dry and concentrated, obtain title compound, be white solid (430.0mg, 95%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.17(d，1H)，7.99(s，1H)，7.50(m，1H)，7.40(d，1H)，7.25(d，1H)，5.98(s，1H)，3.99(s，3H)，2.05(s，3H)。LCMS (method A): [MH] +=328, t R=4.55min.
6-chloro-3-[1-(1-methyl isophthalic acid H-indazole-5-yl)-ethyl]-imidazo [1,2-b] pyridazine (71.3):
Use with the operation identical operations described in compound 69.2 synthetic by 1-(6-chloro-imidazo [1,2-b] pyridazine-3-yl)-1-(1-methyl isophthalic acid H-indazole-5-yl)-ethanol (430.0mg, 1.31mmol), I 2(832.0mg, 3.28mmol) and H 3PO 2(0.72mL 6.56mmol) has synthesized title compound (390.0mg, 91%). 1H-NMR(400MHz，DMSO-d 6)δppm?8.18(d，1H)，7.95(s，1H)，7.83(s，1H)，7.55(m，2H)，7.36(d，1H)，7.28(d，1H)，4.70(q，1H)，3.99(s，3H)，1.74(d，3H)。LCMS (method A): [MH] +=312, t R=5.49min.
6-(1-oxyethyl group-vinyl)-3-[1-(1-methyl isophthalic acid H-indazole-5-yl)-ethyl]-imidazo [1,2-b] pyridazine (71.4):
Use with the operation identical operations described in compound 69.3 synthetic by 6-chloro-3-[1-(1-methyl isophthalic acid H-indazole-5-yl)-ethyl]-imidazo [1; 2-b] pyridazine (390.0mg; 1.25mm ol), tributyl (1-vinyl ethyl ether base) stannane (497.0mg, 1.38mmol) and Pd (PPh 3) 4(145mg 0.13mmol) has synthesized title compound (415.0mg, 86%, 90% purity).LCMS (method A): [MH] +=348, t R=5.86min.
1-(3-(1-(1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethyl ketone (71.5)
Use with the operation identical operations described in compound 69.4 synthetic by 6-(1-oxyethyl group-vinyl)-3-[1-(1-methyl isophthalic acid H-indazole-5-yl)-ethyl]-imidazo [1; 2-b] pyridazine (415.0mg; 1.20mmol) and HCl (1.20mL; 1.20mmol) synthesized title compound (325.0mg, 75%, 88% purity).LCMS (method A): [MH] +=320, t R=5.21min.
(E)-2-(1-(3-(1-(1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1,2-b] pyridazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 71):
Operation identical operations described in use and the embodiment 69 is by 1-(3-(1-(1-methyl isophthalic acid H-indazole-5-yl) ethyl) imidazo [1; 2-b] pyridazine-6-yl) ethyl ketone (20.0mg; 0.06mmol) and Hydrazinecarboxamidederivatives (13.97mg 0.13mmol) has synthesized title compound (14.0mg, 59%). 1H-NMR(400MHz，CDCl 3)δppm?8.33(s，1H)，7.87(m，2H)，7.66(m，3H)，7.32(m，2H)，4.74(q，1H)，4.03(s，3H)，2.24(s，3H)，1.84(d，3H)。LCMS (method A): [MH] +=377, t R=4.70min.
Embodiment 72
(E)-2-(1-(1-((7-fluorine quinoline-6-yl) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001161
5-bromo-N*3*-(7-fluoro-quinoline-6-ylmethyl)-pyrazine-2,3-diamines (72.1):
With N-(7-fluoro-quinoline-6-yl)-methylamine (1.69g, 9.63mmol), 3,5-two bromo-pyrazines-2-amine (2.43g, 9.63mmol) and DIPEA (2.96g, mixture 22.90mmol) are heated to 120 ℃ and reach 10 hours in microwave.To react with DCM and water dilution.Organic layer is used NH 4Na is used in Cl (aqueous solution) washing 2SO 4Drying is filtered and vacuum concentration.Crude product with silica gel chromatography (DCM:MeOH) purifying, is obtained title compound, be yellow solid (2.60g, 69%).LCMS (method E): [MH] +=348/350, t R=5.21min.
6-(6-bromo-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl)-7-fluoro-quinoline (72.2):
To 5-bromo-N*3*-(7-fluoro-quinoline-6-ylmethyl)-pyrazine-2,3-diamines (90mg, 0.26mmol) disposable adding Sodium Nitrite (11.4mg, 0.26mmol) solution in water (1mL) in the solution in acetate (4mL).After 3 hours, solvent removed in vacuo is used NaHCO with resistates in stirring at room 3(aqueous solution) dilution extracts with DCM.Organic layer is used water washing, use Na 2SO 4Drying is filtered and vacuum concentration.With crude product with silica gel chromatography (DCM: MeOH=50: 1) purifying, obtain title compound, be yellow solid (57.0mg, 61%). 1H-NMR(400MHz，DMSO-d 6)δppm9.03(s，1H)，8.94(d，1H)，8.40(d，1H)，8.08(d，1H)，7.84(d，1H)，7.55(dd，1H)，7.53(dd，1H)，6.21(s，2H)。LCMS (method A): [MH] +=359/361, t R=2.23min.
6-[6-(1-oxyethyl group-vinyl)-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl]-7-fluoro-quinoline (72.3):
With 6-(6-bromo-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl)-7-fluoro-quinoline (2.0g, 5.57mmol), Pd (Ph 3P) 4(0.64g, 0.56mmol) and tributyl (1-vinyl ethyl ether base) stannane (4.02g, 11.14mmol) mixture in DMF (50mL) is used nitrogen wash, then in 100 ℃ of heating, stirs 7 hours.Under reduced pressure remove and desolvate, resistates is diluted with DCM, use KF (aqueous solution) and water washing successively, use Na 2SO 4Dry also vacuum concentration.(gradient (DCM: MeOH=50: 1)) purifying obtains title compound, is white solid with silica gel chromatography with crude product. 1H-NMR(400MHz，DMSO-d 6)δppm?9.11(s，1H)，8.93(d，1H)，8.40(d，1H)，8.15(d，1H)，7.83(d，1H)，7.54(m，1H)，6.22(s，2H)，5.50(d，1H)，4.73(d，1H)，4.02(q，2H)，1.40(t，3H)。LCMS (method E): [MH] +=351, t R=5.42min.
1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-ethyl ketone (72.4):
(600.0mg 0.89mmol) stirred 2 hours in 50 ℃ with the solution of 3N HCl (0.1mL) in acetate with 6-[6-(1-oxyethyl group-vinyl)-[1,2,3] triazolo [4,5-b] pyrazine-1-ylmethyl]-7-fluoro-quinoline.Under reduced pressure remove and desolvate.The dilute with water resistates is used NaHCO 3The aqueous solution transfers to the pH value of solution about 8, uses the DCM extracted twice.With the organic layer that merges water and brine wash successively, use Na 2SO 4Drying is filtered and vacuum concentration, obtains title compound, is white solid (630mg, 96%). 1H 1H-NMR(400MHz，CDCl 3)δppm?9.46(s，1H)，8.94(d，1H)，8.11(d，2H)，7.85(dd，1H)，7.41(dd，1H)，6.23(s，2H)，2.79(s，3H)。LCMS (method A): [MH] +=323, t R=2.23min.
(E)-2-(1-(1-((7-fluorine quinoline-6-yl) methyl)-1H-[1,2,3] triazolo [4,5-b] pyrazine-6-yl) ethidine) Hydrazinecarboxamidederivatives (embodiment 72)
To 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-ethyl ketone (30.0mg, 0.09mmol) add in the solution in MeOH (10mL) the Hydrazinecarboxamidederivatives hydrochloride (31.0mg, 0.28mmol).Mixture is heated and stirred overnight in 45 ℃.Under reduced pressure remove and desolvate.(gradient (DCM: MeOH=10: 1)) obtains title compound, is white solid (25.0mg, 67%) with the silica gel chromatography purifying with resistates. 1H-NMR(400MHz，DMSO-d 6)δppm9.91(s，1H)，9.85(s，1H)，8.93(dd，1H)，8.42(d，1H)，8.185(d，1H)，7.83(d，1H)，7.54(dd，1H)，6.20(s，2H)，2.28(s，3H)。LCMS (method A): [MH] +=380, t R=1.98min.
Embodiment 73
Acetate [1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base]-hydrazides
Figure BDA0000151397020001181
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4; 5-b] pyrazine-5-yl]-ethyl ketone (30.0mg; 0.09mmol) and acethydrazide (23.0mg 0.28mm0l) has synthesized title compound (30.5mg, 82%). 1H-NMR(400MHz，DMSO-d 6)δppm?10.83(bs，1H)，9.46(s，1H)，8.93(dd，1H)，8.40(d，1H)，8.19(d，1H)，7.81(d，1H)，7.53(dd，1H)，6.22(s，2H)，2.34，2.14(s，6H)。LCMS (method A): [MH] +=379, t R=2.07min.
Embodiment 74
1N '-[1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base]-methyl carbazate
Figure BDA0000151397020001182
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4; 5-b] pyrazine-5-yl]-ethyl ketone (30.0mg; 0.09mmol) and methyl carbazate (25.2mg 0.28mmol) has synthesized title compound (29.9mg, 77%). 1H-NMR(400MHz，DMSO-d 6)δppm?10.78(bs，1H)，9.38(s，1H)，8.93(dd，1H)，8.41(d，1H)，8.18(d，1H)，7.83(d，1H)，7.54(dd，1H)，6.22(s，2H)，3.78(s，3H)，2.31(s，3H)。LCMS (method E): [MH] +=395, t R=4.64min.
Embodiment 75
Yi Yansuan [1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base]-hydrazides
Figure BDA0000151397020001191
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4; 5-b] pyrazine-5-yl]-ethyl ketone (30.0mg; 0.09mmol) and Isonicotinoylhydrazine (38.3mg 0.28mmol) has synthesized title compound (27.9mg, 64%). 1H-NMR(400MHz，DMSO-d 6)δppm?11.75，11.39(bs，1H)，9.51(s，1H)，8.93(dd，1H)，8.79(m，2H)，8.42(d，1H)，8.20(d，1H)，7.836(m，3H)，7.54(dd，1H)，6.25(s，2H)，2.49(s，3H)。LCMS (method E): [MH] +=442, t R=4.59min.
Embodiment 76
1-[1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base is amino]-imidazolidine-2, the 4-diketone
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1; 2,3] triazolo [4,5-b] pyrazine-5-yl]-ethyl ketone (20.0mg; 0.06mmol) and 1-amino-imidazolidine-2; (28.2mg 0.19mmol) has synthesized title compound (18.0mg, 66%) to the 4-diketone. 1H-NMR(400MHz，DMSO-d 6)δppm?11.45(bs，1H)，9.41(s，1H)，8.93(dd，1H)，8.42(d，1H)，8.21(d，1H)，7.83(d，1H)，7.54(dd，1H)，6.26(s，2H)，4.56(s，2H)，2.45(s，3H)。LCMS (method B): [MH] +=420, t R=1.95min.
Embodiment 77
Propionic acid [1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base]-hydrazides
Figure BDA0000151397020001193
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4; 5-b] pyrazine-5-yl]-ethyl ketone (30.0mg; 0.09mmol) and the propionyl hydrazine (24.6mg 0.28mmol) has synthesized title compound (28.5mg, 74%). 1H-NMR(400MHz，DMSO-d 6)δppm?10.93，10.76(bs，1H)，9.45(s，1H)，8.92(dd，1H)，8.41(d，1H)，8.18(d，1H)，7.83(d，1H)，7.53(dd，1H)，6.22(s，2H)，2.79(q，2H)，2.31(s，3H)，1.09(t，3H)。LCMS (method E): [MH] +=393, t R=4.78min.
Embodiment 78
Nicotinic acid [1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base]-hydrazides
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4; 5-b] pyrazine-5-yl]-ethyl ketone (20.0mg; 0.06mmol) and WS 102 (17.0mg 0.12mmol) has synthesized title compound (17.0mg, 59%). 1H-NMR(400MHz，DMSO-d 6)δppm?11.64，11.38(bs，1H)，9.52(s，1H)，9.05(s，1H)，8.93(dd，1H)，8.78(d，1H)，8.42(d，1H)，8.20(d，1H)，7.84(d，1H)，7.56(m，2H)，6.26(s，2H)，2.49(s，3H)。LCMS (method A): [MH] +=442, t R=2.10min.
Embodiment 79
1-[1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1,2,3] triazolo [4,5-b] pyrazine-5-yl]-second-(E)-the fork base is amino]-imidazolidin-2-one
Operation identical operations described in use and the embodiment 72 is by 1-[3-(7-fluoro-quinoline-6-ylmethyl)-3H-[1; 2; 3] triazolo [4,5-b] pyrazine-5-yl]-(20.0mg is 0.06mmol) with 1-amino-imidazolidin-2-one (28.2mg for ethyl ketone; 0.19mmol) synthesized title compound (18.0mg, 66%). 1H-NMR(400MHz，DMSO-d 6)δppm?9.42(s，1H)，8.93(dd，1H)，8.41(d，1H)，8.20(d，1H)，7.83(d，1H)，7.54(dd，1H)，7.38(s，1H)，6.25(s，2H)，3.86(t，2H)，3.42(t，2H)，2.38(s，3H)。LCMS (method A): [MH] +=401, t R=2.01min.
Embodiment 80
(E)-2-(1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propylidene base) Hydrazinecarboxamidederivatives
3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl)-6-vinyl imidazole is [1,2-b] pyridazine (80.1) also
(400mg adds Pd (Ph to imidazo [1,2-b] pyridazine in solution 1.267mmol) to the 6-chloro-3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) of the degassing 3P) 4(220mg, 0.190mmol) and tributyl (vinyl) stannane (422mg, 1.330mmol).Reaction mixture is heated to 120 ℃ to spend the night.Use NH then 4Cl (aqueous solution) cancellation reaction with the DCM extraction, is used Na 2SO 4Dry also vacuum concentration obtains resistates, and it with silica gel column chromatography (gradient Hex:EA) purifying, is obtained also [1,2-b] pyridazine (168mg, 43%) of 3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl)-6-vinyl imidazole. 1H-NMR(400MHz，DMSO-d 6)δppm?8.09(d，1H)，7.97(s，1H)，7.63(d，1H)，7.55(d，1H)，7.54(d，1H)，7.50(s，1H)，6.84(dd，1H)，6.31(d，1H)，5.72(d，1H)，4.37(s，2H)，3.98(s，3H)。LCMS (method B): [MH] +=308, t R=2.49min.3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-formaldehyde (80.2)
To 3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl)-6-vinyl imidazole also [1,2-b] pyridazine (50mg, 0.163mmol) and add NMO in the mixture of osmium oxide (VIII) (103mg, 8.13 μ mol) (29.5mg is 0.252mmol) at acetone (2ml) and H 2Solution among the O (0.16ml).Reaction mixture is heated to 46 ℃.After stirring 4h, remove and desolvate, add THF (6ml) and H 2The mixture of O (1.5ml) is with the dissolving resistates, and (69.6mg 0.325mmol), stirs 12h with the mixture of gained in 46 ℃ to add sodium periodate then.Use Na then 2SO 3(aqueous solution) cancellation reaction mixture with the DCM extraction, is used Na 2SO 4Drying is filtered and vacuum concentration through Celite, obtains resistates, and it with silica gel column chromatography (gradient Hex:EA) purifying, is obtained 3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-formaldehyde (20mg), yield 38%. 1H-NMR(400MHz，CDCl 3)δppm?10.09(s，1H)，8.07(dd，1H)，7.89(d，1H)，7.74(s，1H)，7.63(m，2H)，7.10(d，1H)，4.54(s，2H)，4.03(s，3H)。LCMS (method A): [MH] +=310, t R=3.95min.
1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propane-1-alcohol (80.3)
To in 0 ℃ 3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-formaldehyde (52mg, 0.168mmol) drip in the solution in THF (4mL) solution of ethyl-magnesium-bromide in THF (1M, 0.336mL).After stirring 16h, reaction mixture is used NH 4Cl (aqueous solution) cancellation with the EtOAc extraction, is used Na 2SO 4Dry.Filter and vacuum concentration through Celite, obtain crude product (14mg, 10%).LCMS (method B): [MH] +=340, t R=2.04min.
1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propane-1-ketone (80.4)
To 1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1; 2-b] pyridazine-6-yl) propane-1-alcohol (13mg; 0.015mmol) add TEA (0.011ml in the solution in DCM (3mL); 0.079mmol) and Dai Si-Martin cross iodine alkane (Dess-Martin periodinane) (40mg, 0.094mmol).Behind stirring at room 10min, use Na 2SO 3(aqueous solution) cancellation reaction extracts with DCM.Separate organic layer, use Na 2SO 4Dry also vacuum concentration obtains resistates, and it with silica gel column chromatography (gradient Hex:EA) purifying, is obtained 1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propane-1-ketone (4mg, 74%).LCMS (method A): [MH] +=338, t R=5.08min.
(E)-2-(1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propylidene base) Hydrazinecarboxamidederivatives (embodiment 80)
Be similar to the synthetic of embodiment 1 and prepared title compound, be white solid by 1-(3-((6-fluoro-1-methyl isophthalic acid H-indazole-5-yl) methyl) imidazo [1,2-b] pyridazine-6-yl) propane-1-ketone. 1H-NMR(400MHz，DMSO-d 6)δppm?9.89(s，1H)，8.16(d，1H)，7.95(m，2H)，7.67(d，1H)，7.61(s，1H)，7.52(d，1H)，4.40(s，2H)，3.96(s，3H)，2.85(q，2H)，0.91(t，3H)。LCMS (method B): [MH] +=395, t R=1.72min.
Embodiment 81
(E)-2-(1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-yl) ethylidene) Hydrazinecarboxamidederivatives
Figure BDA0000151397020001231
6-bromo-1,2,4-triazine-3-amine (81.1)
With 3-amino-1,2, (50.0g, 521mmol) mixture in water (6000mL) is cooled to 0-5 ℃ to the 4-triazine.(70mL 1.30mmol) reaches 1h to dripping bromine in reaction mixture.Then with mixture in 0-10 ℃ of stirred overnight.In reaction, add saturated Na 2SO 3The aqueous solution is neutralized to pH=12 with the 6NNaOH aqueous solution with mixture.Use the dichloromethane extraction mixture, use Na 2SO 4Dry.Solvent removed in vacuo obtains 50.0g (54%) title compound, is yellow solid. 1H-NMR(400MHz，d 6-DMSO)δppm?8.40(s，1H)，7.47(s，2H)。LCMS (method B): [MH] +=175/177, t R=0.328min.
6-(1-vinyl ethyl ether base)-1,2,4-triazine-3-amine (81.2)
With 6-bromo-1,2,4-triazine-3-amine (780mg; 4.46mmol) at N, the solution in the dinethylformamide (50mL) with four (triphenyl phosphine) palladium (0) (258mg, 0.22mmol), N; The N-diisopropylethylamine (2284mg, 11.14mmol), lithium chloride (661mg, 15.6mmol) with vinyl tri-n-butyl tin (2093mg; 5.79mmol) handle, will react on 120 ℃ of heating 2h.Reaction mixture is cooled to room temperature and vacuum concentration solvent.Dilute resistates with methylene dichloride, use the KF solution washing.Crude product with silica gel flash chromatography method purifying, is used the ethyl acetate/hexane gradient elution, obtain 380mg (51%) title compound, be yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?8.48(s，1H)，5.41-5.39(m，3H)，4.36(s，1H)，3.98(q，2H)，1.43(t，2H)。6-((2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) imidazo [1,2-b] [1,2,4] triazine-7-yl) methyl) quinoline (81.3)
With 6-(1-vinyl ethyl ether base)-1,2, and 4-triazine-3-amine (120mg, 0.72mmol), (317mg, 1.44mmol) solution in terepthaloyl moietie (8mL) stirs 2h in 140 ℃ to 2-chloro-3-(quinoline-3-yl) propionic aldehyde.Reaction mixture is cooled to room temperature, uses saturated Na 2CO 3Aqueous solution neutralization and dilute with water are used ethyl acetate extraction, use Na 2SO 4Dry.Solvent removed in vacuo with silica gel flash chromatography method purifying, is used the ethyl acetate/hexane gradient elution with resistates, obtains 135mg (54%) title compound, is yellow solid.LCMS (method B): [MH] +=348, t R=2.03min.
1-(7-(quinoline-6-ylmethyl) imidazo [1,2-b] [1,2,4] triazine-2-yl) ethyl ketone (81.4)
(130mg, 0.37mmol) solution in 3NHCl (5mL) stirs 0.5h in 90 ℃ with 6-((2-(2-methyl isophthalic acid, 3-dioxolane-2-yl) imidazo [1,2-b] [1,2,4] triazine-7-yl) methyl) quinoline.Reaction mixture is cooled to room temperature, uses saturated Na 2CO 3Ethyl acetate extraction is used in aqueous solution neutralization, uses Na 2SO 4Dry.Solvent removed in vacuo obtains 85mg (75%) title compound, is yellow solid. 1H-NMR(400MHz，CDCl 3)δppm?9.06(s，1H)，8.91(d，1H)，8.12(t，2H)，8.04(s，1H)，7.74-7.71(m，2H)，7.48-7.39(m，1H)，4.60(s，2H)，2.70(s，3H)。LCMS (method B): [MH] +=304, t R=1.81min.
The C-Met enzyme assay
In the tyrosine phosphorylation assay method that with antibody is the basis, tested a large amount of compound of the present invention as follows.
EPK cMET analyzes (Profiling) assay method:
Use purified recombinant GST-fusion rotein to set up the EPK kinase assay that is used for the cMET receptor tyrosine kinase, said albumen contains the cytoplasmic structure territory of this enzyme.With affinity chromatography GST-cMET (969-1390) has been carried out purifying.
This kinase assay is with LanthaScreen TMTechnology is the basis.LanthaScreen TMThe interactional time resolved fluorescence resonance energy that is to use lanthanide chelate to measure between the various binding partners shifts (TR-FRET) detection.In the TR-FRET kinase assay, lifelong lanthanon donor kind and antibody yoke close, and said antibodies specific ground combines with phosphorylation product with the kinase reaction of suitable acceptor fluorophore tagged.This antibody-mediated interaction makes lanthanon donor and acceptor near so that resonance energy takes place to be shifted, thereby causes detectable FRET signal to increase.
Kinase reaction is that the total reaction volume with 10.05 μ L is carried out in 384 hole microtiter plates.Test compound like the suitable test concentrations of each hole 0.05 μ L of said usefulness under " preparation of diluted chemical compound liquid " item has prepared assay plate.Through being mixed with 5 μ L enzyme-substrate mixtures (being made up of kinases and substrate), 5 μ L ATP solution begin reaction.Final concentration in the kinase reaction is 25mM Tris/HCl, 1mM DTT, 0.025% polysorbas20,10 μ M Trisodium vanadates, 0.25%BSA, 0.5%DMSO, 10mM MgCl 2, 3mM MnCl 2, 2 μ M ATP, 50nM Fluorescein-PolyEAY and 0.3nM enzymes.
To react on incubated at room 60 minutes, stop damping fluid (50mM EDTA, 0.04%NP40,20mM Tris/HCl) stopped reaction through adding 5 μ L.
Subsequently, in the reaction that stops, adding 5 μ L and detect mixture (50mM Tris/HCl, 2mMDTT, 0.05% polysorbas20,20 μ M Trisodium vanadates, 1%BSA, 1nM Tb-PY20 antibody)., in Perkinelmer Envision fluorescence reader, plate is measured after 45 minutes in incubated at room in the dark.Compound all is (the terminal point measurements) that obtained by the development of linear curve and confirmed by single reading to the effect of enzymic activity in all are measured.
The result is summarised in the following table.In this enzyme assay, " activity " of the present invention compound have less than 5000nM, particularly less than 3500nM, preferably less than 1000nM, be more preferably less than 500nM, most preferably less than the IC50 of 10nM.
GTL16 cells survival amylograph:
GTL16 clone derives from patients with gastric cancer.Because gene amplification GTL16 expresses high-caliber cMet receptor tyrosine kinase.The growing height of GTL16 depends on the cMet kinase activity; Therefore it is monitored the cytoactive of cMet SU11752 as the cell base assay method.
The GTL16 cell is seeded in 96 orifice plates and at 5%CO with 5000 cells/well/90 μ L in the DMEM substratum that contains 10%FBS and 1%Pene & Strep 2In the incubator in 37 ℃ of incubated overnight to adhere to.The 10-times of serial dilutions that in cell, adds compound with 10 μ L/ holes.Final mensuration volume is 100 μ l/ holes.With assay plate at 5%CO 2Hatched 24 hours in 37 ℃ in the incubator.Use CellTiter Glo (Cat#G7573Promega) to measure the viability of cell according to the scheme of retailer's suggestion.In brief, plate is cooled off 10min in room temperature, in each hole, add 100 μ l CellTiter Glo reagent.With plate jolting 10min.In from the Envision of Perkin Elmer, the chemoluminescence light unit is carried out reading.All tests are all carried out in triplicate.Use the Spotfire computed in software to go out IC 50
The inhibition of table 1 compound is active
Figure BDA0000151397020001261
Figure BDA0000151397020001271

Claims (19)

1. formula (I) compound or its pharmacy acceptable salt:
Figure FDA0000151397010000011
Wherein
Y is C or N;
X is CH or N;
B is CH or N;
A is a ring;
Condition is
When X is CH and B when being N, ring A is ring Ai or ring Aii;
Figure FDA0000151397010000012
When X is N and B when being N, ring A is Aiii;
Figure FDA0000151397010000013
And when X be that N and B are that N or X are N and B when being CH, ring A is Ai;
R 1Be group i:
Figure FDA0000151397010000022
R wherein 5It is heteroaryl 1,
Heteroaryl 1Be to comprise 1,2,3 or 4 9-or first undersaturated or undersaturated bicyclic groups of part of 10-that is independently selected from the ring hetero atom of N, O and S, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1, wherein heteroaryl 1Optional by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen;
R 6Be hydrogen, deuterium, OH, methyl or halogen;
R 7Be hydrogen, deuterium, halogen or (C 1-C 3) alkyl, wherein said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen;
Perhaps R 6And R 7Form cyclopropyl with the carbon that they connected, wherein said cyclopropyl is optional to be replaced by methyl;
R 2Be hydrogen, NH 2Or (C 1-C 4) alkyl, wherein said (C 1-C 4) alkyl is optional by one or more OH, NH of being independently selected from 2Replace with the substituting group of halogen;
R 3Be hydrogen ,-CONH 2,-CONH (C 1-C 4) alkyl ,-the CONH phenyl, the phenyl in the wherein said CONH phenyl optional by one or more halogens ,-(C 1-C 4) alkyl ,-CO (C 1-C 4) alkyl ,-CO 2(C 1-C 4) alkyl, phenyl, heteroaryl 2,-CO heteroaryl 2,-CSNH 2,-CSNH (C 1-C 4) alkyl ,-the CSNH benzyl ,-SO 2(C 1-C 4) alkyl or-COCH 2Heterocyclic radical 1Replace said heterocyclic radical 1Optional by (C 1-C 3) the alkyl replacement;
Heteroaryl 2Be to comprise 1,2,3 or 4 first undersaturated or undersaturated monocycle of part or bicyclic groups of 5-to 10-that is independently selected from the ring hetero atom of N, O and S, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1, wherein heteroaryl 2Optional by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen;
Heterocyclic radical 1Mean the saturated or undersaturated monocyclic groups of part of 5 or 6 yuan of comprising 1 or 2 ring hetero atom that is independently selected from N, O and S;
R 4Be hydrogen or (C 1-C 3) alkyl;
Perhaps R 3And R 4Form 5 or 6 yuan the saturated or undersaturated monocyclic groups of part with the nitrogen that they connected, said monocyclic groups comprises 1 ring N atom, R 3And R 4Be connected with this N atom, said monocyclic groups is optional to comprise 1 other ring hetero atom that is independently selected from N, O and S, wherein said monocyclic groups by one or two=the O substituting group replaces.
2. the compound described in the claim 1 or its pharmacy acceptable salt, wherein
B is N;
Y is C or N;
X is CH or N;
Condition is when X is CH, and ring A is ring Ai or ring Aii;
Figure FDA0000151397010000031
And when X was N, ring A was Aiii;
All the other substituting groups in the claim 1 definition.
3. the compound described in claim 1 or the claim 2 or its pharmacy acceptable salt, wherein R 5It is heteroaryl 3, heteroaryl wherein 3Be to comprise the 9-of 1 or 2 ring N atom or undersaturated or the undersaturated bicyclic groups of part, the wherein heteroaryl of 10-unit 3Optional by one or more substituting groups replacements, said substituting group is independently selected from halogen, OH and (C 1-C 3) alkyl, said (C 1-C 3) alkyl is optional by one or more substituting groups replacements that are independently selected from OH and halogen.
4. the compound described in the claim 3 or its pharmacy acceptable salt, wherein R 5Be indazolyl or quinolyl, it is optional by one or more halogen and (C of being independently selected from 1-C 3) substituting group of alkyl replaces.
5. the compound described in the claim 4 or its pharmacy acceptable salt, wherein R 5Be indazole-5-base, it is replaced by the methyl substituting group on 1, and optional further by 1 or 2 fluoro substituents replacement, perhaps R 5Be quinoline-6-base, it is optional by 1 or 2 fluoro substituents replacement.
6. compound or its pharmacy acceptable salt, the wherein R described in any one of the claim 1-5 6Be hydrogen, deuterium or halogen.
7. compound or its pharmacy acceptable salt, the wherein R described in any one of the claim 1-6 7Be hydrogen, deuterium, halogen or methyl.
8. compound or its pharmacy acceptable salt described in any one of the claim 1-7 wherein worked as R 6And R 7When inequality was hydrogen, formula (I) compound was (S) enantiomorph.
9. compound or its pharmacy acceptable salt, the wherein R described in any one of the claim 1-8 2Be hydrogen or methyl.
10. compound or its pharmacy acceptable salt, the wherein R described in any one of the claim 1-9 3Be hydrogen ,-CONH 2,-CONHCH 3,-CONH phenyl, the phenyl in the wherein said CONH phenyl optional by one or more halogens ,-(C 1-C 4) alkyl ,-COCH 3,-CO 2CH 3, phenyl, benzo
Figure FDA0000151397010000041
Azoles base, heteroaryl 4,-CO heteroaryl 4,-CSNH 2,-CSNH (C 1-C 2) alkyl ,-the CSNH benzyl ,-SO 2Me ,-COCH 2Morpholinyl, COCH 2Piperidyl or-COCH 2Piperazinyl replaces, and said piperazinyl is optional by one or more (C 1-C 3) alkyl replacement, wherein heteroaryl 4Be to comprise 1,2,3 or 4 undersaturated monocyclic groups of undersaturated or part of 5 or 6 yuan that is independently selected from the ring hetero atom of N, O and S, the sum that wherein encircles the S atom is no more than 1, and the sum of ring O atom is no more than 1.
11. the compound described in the claim 10 or its pharmacy acceptable salt, wherein R 3Be-CONH 2
12. compound or its pharmacy acceptable salt, the wherein R described in any one of the claim 1-9 3And R 4Nitrogen with they connected forms
Figure FDA0000151397010000051
Oxazolidone, Oxazolidinedione, imidazolidone or imidazolidimedione.
13. compound or its pharmacy acceptable salt described in any one of the claim 1-12, it is used in medical science or the medicine.
14. compound or its pharmacy acceptable salt described in any one of the claim 1-12, it is used to treat the tyrosine kinase mediated disease of one or more c-Met.
15. compound or its pharmacy acceptable salt described in any one of the claim 1-12, it is used to treat proliferative disease or inflammatory conditions.
16. the compound described in any one of the claim 1-12 or its pharmacy acceptable salt purposes in the preparation medicament, said medicament is used to treat the tyrosine kinase mediated disease of one or more C-Met.
17. treat the obstacle relevant with c-Met or the method for illness, it comprises formula (I) compound or its pharmacy acceptable salt of using significant quantity to its individuality of needs.
18. pharmaceutical composition, it comprises formula (I) compound or its pharmacy acceptable salt described in any one of the claim 1-12, and at least a pharmaceutically acceptable carrier and/or thinner, and optional one or more other therapeutical agents that comprises.
19. with formula (I) compound or its pharmacy acceptable salt described in any one of the claim 1-12 of one or more other therapeutic activity agent combination.
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